WO2016042089A1 - Macrocyclic lrrk2 kinase inhibitors - Google Patents

Abstract

The present invention relates to novel macrocyclic compounds of formula (I) and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of LRRK2 (Leucine-Rich Repeat Kinase 2). Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine or diagnostic agent, in particular for the treatment and/or diagnosis of diseases characterized by LRRK2 kinase activity such as neurological disorders including Parkinson's disease and Alzheimer's disease.

Description

^{-1- MACROCYCLIC LRRK2 KINASE INHIBITORS}

F^ie

5 ^T

K ^coh

i^{nmeld ap p o sor}

e^{uef 2ns th )de}

.^{snet in M a i}

o^{cnv rtve einen ognttiio ve aon r,sn}

t^{h k r}

e^ienlaa

p^ste

r^es

e^{s ien to}

n^{htib n}

i^{niotvovresl, m ina pcraorctiycculliacr c aosm ipnohuibnitdosrs an odf L cRoRmKp2os (iLtioenuscin ceo-nRtaicihnin Rgep seaaidt compounds, as well as methods of uesnition provides processes for the preparation of the disclosed particular for the treatment and/or diagng them, for instance as a medicine or diagnostic agent, in as neurological disorders includin nosis of diseases characterized by LRRK2 kinase activity such 10 g Parkinson’s disease and Alzheimer’s disease.}

B ^{Paarckkingsroonu’nsd di osfea thse invention}

o^{f dopaminergic e is a degenerative disorder of the central nervous system. It results from the death 15 symptoms are mo nveeumroennet-s in the midbrain. In the early stages of the disease the most obvious L aadtvearnc oend a slstaoge csog onfit tihvee related such as shaking, slowness of movement and difficulty with walking.}

d ^{and behavioural problems arise, with dementia commonly occurring in the within the last deca isease. Although Parkinson’s disease is generally considered to be sporadic, linked to Parkinsond’es, a d few mutations in the LRRK2 (leucine rich repeat kinase 2) gene have been dardarin, is a member ofi tsheeas leeuc (iWneO-2006068492 and WO2006045392). LRRK2, also known as 20 p} ₂ ^a ₀ ^r _L ^tic _R ^u _R ^la _K ^r ₂ ⁱⁿ _m ^t _u ^h _t ^e _at ^b _io ^ra _n ⁱ _s ^n, _in ^bu _fa ^{t also in otherirc this rseupeesa tth krionuagsheo fuatm thiley b hoadviyn.g R mesixeeadr-clhineerasg hea kviena idseen aticfiteivdit oy,ve inr} c_{o-segregates with autmilies with late-onset Parkinson Disease. For example the G2019S mutation Parkinson’s disease casoessom aanld d 3ominant Parkinsonism and accounts for about 6% of familial 25 mutation occurs in the highly conse%rve sdporadic Parkinson’s disease cases in Europe. The G2019S G su2b0s1ti9tuStio mnusta attio an s mecaoyn hda rveesi adnue ef Rfe1c4t4 o1n ki}

a _{kniansaese do amctaivinity a (nWdO it2 h0a0s60 th6e8r4e9fo2r)e. F buerethne prmosoturela,t aemdi tnhoat a tchied been shown to elevate LRRK2 kinase activrie also associated with Parkinson’s disease and have also in transgenic mouse models (Li, Y et al.20ty0.9 Over-expression of the mutant LRRK2 protein R1441G symptoms of Parkinson’s disease as well as re,d Nature Neuroscience 12:826-828) is associated with 30 L coRnRdKit2ion csou cldha arlascote priozseidtive blyy r reegduulaceted d dooppaammineuc reedle daospea amninde h raevleeas peo,te snutgiagles uttiinlitgy th inat tr inehaitbmiteonrst o off associated with drug addiction; Tauopathy diseiane levels, such as withdrawal sypmtoms/relapse disease, Pick’s disease, corticobasal degeneses such as Alzheimer’s disease, argyrophilic grain 35 Parkinson’s disease. Two further mutations in LraRtion; inherited frontotemporal dementia; and t prraonvsiditieon e fvriodmen mceild th caotgn inithiviebit iomrpsai ormfe LnRtR toK2 Alz khineaimRK2 have been clinically associated with the ser’s disease (WO200714979). These data further dementias and related neurodegenerative disorders.e activity could be useful for the treatment of} ^{-2- T thheursa,p piehsar inma nceoulroogdiceagle innehribaittiivoen d oifs LorRdRerKs2, s kuincase is an attractive strategy towards mechanism-based was therefore an object h as Parkinson’s disease and Alzheimer’s disease. It sa of the present invention to provide compounds and compositions comprising 5 Udo s}

n^eni

u^{tirll c}

o^{n tom}

a^dlapo

d^yu

i^{s sn}

o^ed

r^vs

d^e,

e^{r a}

r^ac

s^lt

, ⁽ⁱ

iⁿⁿ

n^{ogn a}

p^{-am i}

r^tan

i^cch

u^ri

l^ob

a^cit

r^yos

A^{crllizc o}

h^)f

e ^{p L}

i^myRreaR

r^zK

’^o2

s^{lo k}

d^pi

i^syn

e^raiamse

s^{iedsi.n aensd/ hoarv Pea brkeiennso snuggested for the treatment of EP1908764, US6194410, EP1354884, EP0729758 and U ’s disease (see for example compounds disclosed in said references have S6194410). However, none of the 10 Furthermore, the currently dev been shown to have LRRK2 inhibitory activity.}

n _W ^e _O ^ur ₂ ^o ₀ ⁿ ₀ ^a ₉ ^l ₁₂ ^d ₇ ^is ₆ ^o ₅ ^rd ₂ ^e _, ^r _W ^s, _O ^d ₂ ^o ₀₁ ^{not ceolmopperdise LR mRaKc2ro kcinyaclsice i pnyhriabzitoolrosp,y inrim paidritniceula mro thieotisees fo (sre thee f torera etmxaemntp olef} N_{onetheless, there is a1 c0o3n8t572).}

t_{reatment of inuing need to design and develop LRRK2 kinase inhibitors for the pharmaceutic naellyur aocncaelp dtiasbolrede crosm.p Woesit hioanvse a ncocword foinugnd to th thaits th ineve mnaticrocyclic pyrazolopyrimidines and 15 several neuronal disorders associated with LRRK2 kinase activity. on are useful for the treatment of S WUeM hMavAeR sYur OpFris TinHgEly I fNoVunENTION 20 in r d that the macrocyclic compounds described herein act as kinase inhibitors, I tn p}

a_{u aa}

t_{om ftiirc}

e_su

r_tla

, _{r or}

a_{b L}

c_jeeR

m_cRtiiK

c_{v,e2 k}

m _tehin

t_eas

a_{b pe}

o_{rle in}

i_tsh

e_ei

,_nb

p_tito

r_{o inrs}

-_v.

o_{ern ptrioendru pgro,v siadlet,s hy adr caotem,p No-uonxdide o ffor Fmo,rm oru slaolv Ia oter t ahe sreteorfe,oisomer,}

W^{here si}

^{I 25 R1 isRenlected -S-C- lkyl, -NR9R10, -(C=O)-R4}

s^{a4i,d -S -CO2}

1^{-- , -(C=S)- 6R f}

a^l4r

k^,o

y ^-m

l^{C iN–}

s^,H

o ^-pN,–h

t^iRo9n-a

a^Slo

l^O,

l^{y2 --O}

a^RH

n^{4d,, - inC -C- d3e-6pcyl}

e^ck

n^ly

d^ol

e^a,

n^{l -kO}

t^{ly-C- lkyl,}

y^{l, s -uOb-sCt3it-u6cteydclo wailtkhyl f,ro -Amr11 an tod 3–H seutb1s;t wituheenretsin s eealeccht of from–ha} _e ^l _d ^o, _to ^-O _Z ^R35

1 _o ^, _r ^-N _Z5 ^R _a ¹¹ _n ^R _d ¹² _i ^, _s - _s ^O _e-_l ^C _ec ^{1- ed} R _t ⁶ _e ^a _d ^lky _fr ^l _o ^, _m ^and _–H ^-S _,-_– ^C _h ¹ _a ^-6

5 _{is attach lo} ^a _, ^lk -^y _O ^l; _{H, -C1-6alkyl, -O-C1-6alkyl, -S}

3_{0 NR6R7, -(C=O)-R8, -(C=S)-R8, -SO2-R8}

6_{a, -CN, -NR6-SO2-R8, -C3cycloalkyl, -O-C3-6cycl-oCa1lk-6yall,ky -Al,r5 - a tond 3 s–uHbest -6}

t_{5i;tu wehnetsre sinele ecatcehd o frfo smai–dh -aClo1-, -OlkRyl36 is, - oNpRti2o3nRa2l4l,y - aOn-dC1 in-6daelkpyel,n adnednt -lSy- sCu1b-6satliktuytle;d with from 1} ^{-3- R2 is o selected from–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl is apntdio -nNaRlly13 and independently substituted with from 1 to 3 substituents selected from–halo,–OR27, 5 R3 is o selectedR f1r4o;m–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl is} a^p _n ^t _d ^io -ⁿ _N ^a _R ^lly ₁ ^{and independently substituted with from 1 to 3 substituents selected from–halo,–OR28,} R ₅

4 _{and R8 areR1 e6a;ch independently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - R, RN7R,1 R7R18}

9_{, R,1 -0C,3 R-6}

1_{c1y,c Rlo1a2,lk Ry1l,3, -O R-1C3-6}

4_{, Rc15y,c Rlo1a6l,kyl, -Ar4 and -Het4}

6 _;

1₀ ⁶ _{and R are each independently selecte Rd17 f,ro Rm18,– RH1,9 -,h Ra2lo0,, R =2O1,, R -O22H,, R -2C3,1- R24}

6_{alk,y Rl,3 -1O, R-C32 3}

1_{,-6 Ralk3,yl R,3 -4 36 S,- RC35}

1- i^{nadlkeypl,en -dCe3n-6tclyyc sluobaslktiytul,te -dA wr6ith an frdom– 1He tot63; s wuhbesrtietuinen etsac shele octfed sa friodm -–Ch1-6alkyl is optionally and C1-6alkyl, -C3-6cycloal alo,–OH, -O-C1-6alkyl, -S- R kyl, -Het6, -Ar6 and–NR37R38}

2^{7 and R28 are each inde ;}

1^{5 R -Cnd3-6 Rcyclre each indeppeennddeennttllyy s seelelecctteedd f frroomm––HH,, - -Ch1a-6laol,k -yOl,H -C, -3C-6c1-y6callokayll,ky -Ol a-Cnd1-6 -aHlkeyt2}

3^{7 a 38 a l,: -S-C1-6alkyl, X oalkyl, -Ar7 and–Het7}

1 ^{is ;}

N ^{sRe3l-e,c atendd f -rOom-; w–Che1-r6eailnky el-a,c–hO o-Cf1 s-6aaidlky -Cl-,1-–6aSlk-Cyl1--6 iaslk oyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-6alkyl-, - from 1 to ptionally and independently substituted with 20 X2 is an}

N ^sd

R^{e2l - -eN}

,^cR

a^te3

n^{d3R 3 d f -r3}

O^{o4 s;ubstituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -phenyl, m-; w–Che1-r6eailnky el-a,c–hO o-Cf1 s-6aaidlky -Cl-,1-–6aSlk-Cy1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-6alkyl-, - f l- is optionally and independently substituted with -rNoRm 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6}

3 ^{alkyl, -phenyl and} _{25 Ar} ¹

1_{, c Aorm4,p A} ^R _r ³²

5_, ^; _{Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally beingr oispintigon 1al tloy 3 an hde itneroatoms selected from O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and Ar7 OH, -C1-6alkyl, -O-C1-d6aelpkeynl,dently substituted with from 1 to 3 substituents selected from–halo, - optionally and independently su -Sb-sCti1tu-6taeldky wl,i and–NR19R20; wherein each of said -C1-6alkyl is 30 Het1 f,ro Hmet21, H toet 34, h Heetet5r,o Haetot6m,s an sdel Hecette7d ar fero emac Oh, itnh}

N_{d fero}

a_{pmen 1de tont 3ly - aha 3l-o; to 10-membered heterocycle having Het6, a nd S; wherein each of said Het1, Het2, Het4, Het5, from–hnadlo H,e -Ot7H is,– optionally and independently substituted with from 1 to 3 substituents selected each of said -C1-6alC1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

_{(C=O)-C1-6alkyl, and -NR21R22; wherein 35 Het8 w ishle a}

e_{rce 3}

t_{ei-n to}

d _{f s 1}

r_a0

o_imd-m

– _He

h_em

a_{t8bkey lo, isrle isd o -O oHp hp ,tet}

i_{–otieo Cnrn}

a_{oa 1-l6lcl substittd ith f 1 to 3 -halo;}

y_ylyc

a_{lk al aen ynl,d hda i -C ivn}

n_{id 1dnependently -6eg}

a_{p f}

l_kero

y_nm

l_{edne 1}

e_{n,t tl -yo 3}

C_{1 s-6u h}

a_be

l_st

k_tyilt-uCtet

3_{-d6cy wciltohl}

a_{l fkrot}

y_lmd

, _{-C 1 from O, N and S; se 3-6 tcoyc 3lo saulkbysl,ti -tuOe-nCt1s-} 6 ^{-Cal1k-y6al,lk -ySl-C is1 o-6patlikoynl,a =llyO a, -}

^{(dC i=Od)-pC1-6dalkytll, -C1-6alkyl-O-C1-6alkyl and -NR21R22; wherein each of said} _{40 Z1, Z w2,h Zer3e,i Zn whnedn Z R1}

5 _{ar–eH e,a thch indte lpentdently h} ^{y s}

s_ete ^u

l_er ^b _o ^s

c_a ^ti

t_et ^t _o ^u

d_m ^ted

f_{ro omf} ^w _H ^it

C_e ^h _{t a8} ^fr

n _i ^o _s ^m

d _{a Nt} ¹ _t;a ^t

a_c ^o

n_h ³

d_ed ^-h _t ^a _o ^lo _X ^; ₂

4 _a ^{-4- A1 and A2 are each independently selected from C and N.}

I ^{rnac peamrtiicc,u mlaer,ta tbhoeli pter,e pseron-t o inrv perendtiorung, p sroavlti,d heys a compound of Formula I or a stereoisomer, tautomer, 5 R1 is} _R ^{selected from–H,–halo, -OH, -C1-6alkdyrla,t -eO,- NC-1o-6xide form, or solvate thereof, wherein}

4_{, -SO2-R4, -CN, -NR9-SO2-R4, -C3-6cycloa} ^{alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, -(C=S)-} s_{aid -C1-6alkyl is optionally and independlkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; wherein each of from–halo, -OR35, -NR11R12, -O-C1-6alkyl,ently substituted with from 1 to 3 substituents selected 10 R5 isS a-Ctta1-c6ahlekdyl, to - ZN1R o6rR Z5}

7_{, a -(nCd= iOs) s-eRl8e,ct -e(Cd= frSo)m a}

-_R–n

8_Hd

,_{, - -S–Sh- OaC}

2_{l-o1- R,6a}

8 _-,Olk

-_Hyl

C_,;

N _{-,C1 --N6aRlk6-ySl,O -O2-HR,8, -C -C1-6}

3_{a-6lckyycl,lo -Oal-kCy1l,-6a -Olk-yCl,3 --} 6 ^{scuybcslotitaulkteydl, w -Aithr5 fr aonmd 1– tHoe 3t5; su wbhsteitrueeinnts ea scehlec otefd sa friodm -C–h1-a6alolk,y -lOR is36 o,p -NtioRn2a3Rlly24, a -nOd- independently S-C1-6a C1-6alkyl, and - 15 R2 is op steiolencatl}

l^eky

l^ydl;

a ^{fnrodm ind–eHp,e -nhdaelon,tl -yO sHu,bs -Ctit1u-6taeldky wl,it ahn fdrom -C31-6 tcoyc 3lo saulbkyslt;itu weherein each of said -C1-6alkyl is} i_s ^an

o_{p s} ^{d nts selected from–halo,–OR27,} R _teiol -_e ^N

n_c ^R

a_tle ¹

l_yd ^3R

a _f ¹

n_r ⁴

3 _o ^;

d_{m ind–eHp,e -nhdaelon,tl -yO sHu,bs -Ctit1u-6taeldky wl,it ahn fdr -C3-6cycloalkyl; wherein each of said -C1-6alkyl is 20 a om 1 to 3 substituents selected from–halo,–OR28, R4 a Nnn}

R_ddN

1 _{R - 7R8R}

1_{8 a1}

,_r5

-_eR1

C _e6

3_-a;

6_{ccyhcl ionadlekpyle,n -Ode-Cnt3ly- selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - R 6}

6_{, R an7,d R R9, R a10re, R e1a1c,h R1 in2,d Rep13e,n Rd1e4n,t Rc}

l_{y1y5 s,cl}

e _Roa

l_e1c6l

t_,ky

e _Rl,

d_{17 - fr,A}

o _Rr4

m_{18 a}

–_,n

H _Rd

,_{1 -9H}

-_{,h Ret4}

a_l2o0;

,_{, = RO21,, - RO2H2,, R -C23}

1_{,-6 Ra2lk4,yl R,3 -1O,- RC32}

1_{-,6a Rlk33yl R,3 -4 36 S,- RC35}

1-^{25 6}

C ^ina

1^dlk

-^6ey

a^pl,

l^{ekyn - ldC}

,^e3

-^Cn-6tc

3^l-yyc

6^{c sl}

y^uo

c^ba

l^oslk

a^tiy

l^tkul,

y^{te - ldA wr6ith an frdom– 1He tot63; s wuhbesrtietuinen etsac shele octfed sa friodm -–Ch1a-6laol,ky–lOH is, - oOp-tCio1n-6aalllkyyl, a -nSd- R and R, are each ind , -Het6, -Ar6 and–NR37R38}

2^{7 28 ;}

R ^{nd R38, are each indeeppeennddeently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2}

3^{7 a : 30 -C3-6cycloalkyl, -Ar7 ntly selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, X1 is selected from–C1- a6anldky–lH-,e–t7O;-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-6alkyl-, - X2 is N}

N ^sR

R^{e3l-e acntedd– fOro-m;–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-6alky} _{35 cr2}

4_,-,

p _{A a} ^{l-, -} A_{r1, A rrn5,d A -Or6-,; and Ar7 are ea}

b_{oeming oispintigon 1al tloy 3 an hde itnedroeapteonmdsc}

e_{n sh}

t_{e i}

l_ylned

s_{cuteependently a 5- to 10-membered aromatic cycle optionally bdst fitruom O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and Ar7 OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl,ted with from 1 to 3 substituents selected from–halo, - optionally and independently substituted with an frdom–NR19R20; wherein each of said -C1-6alkyl is 40 Het1 f,ro Hmet21, H toet 34, h Heetet5r,o Haetot6m,s an sdel Hecette7d ar fero emac Oh, in Nde apnedn 1o}

S_{de t}

;_{n wt 3lhy - e aha}

r_{e 3l}

i_{n-o; t eoa 1c0h-m ofe smabider Hedet h1,e Hteerot2c,y Hcelet4 h,a Hveint5g,} ^{-5- H froemt6,– ahnadlo H,e -Ot7H is,– oCp1ti-o6anlaklylyl, - aOn-dC i1n-6daelkpyeln,d -Se-nCtl1y-6 saulkbysl,tit =uOte,d -}

^{( wCi=thO) fr-oCm1-6a 1lk tyol, 3 an sudb -sNtiRtu2e1Rnt2s2; s welected each of said -C1-6alk} _e ^{yl is optionally and i ; herein} 5 _{Het8 w is a 3} ^{ndependently substittd ith f 1 to 3 -halo} s_{ehleercetei-n to}

d _{f s 1}

r_a0

o_imd-m

– _He

h_em

a_t8b

l_{o, isred}

-_{O oHp h}

,_tei–ote

C_nrao

1_{-l6lcyycle having from 1 to 3 het t l td from O, N and S; alk aynl,d -C in1d-6eaplkeynledneen,tl -yC1 s-6uablsktyilt-uCte3-d6}

6 _{cy wciltohal fkroylm, -C 13-6 tcoyc 3lo saulkbysl,ti -tuOe-nCt1s-} -^{Cal1k-y6al,lk -ySl-C is1 o-6patlikoyl, =O, -}

^{(C=O)-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and -NR21R22; wherein each of said wherein when R1n iasll–yH a, tdh idtp l dt tly s huebtesrtoituatteodm w oifth H ferot8m is 1 a tto 3 -halo;}

1^{0 Z A1}

1^{, a Zn2d, Z A3}

2^{, a Zr4e a enadc Zh5 in are each independently selected from C and N; atnadched to X2}

d^{ependently selected from C and N.}

M^{ore tau intom paerrt,ic rauclaerm tihce, m perteasbeonlitte i,n pveron-ti oorn pr perdorvuidge,s sa alt, c hoymdrpaoteu,n Nd-o oxfid Feo frmula I or a stereoisomer, 15 whe orm, or solvate thereof, R1 isre}

R^{4 sin}

,^{e -leScOte2-dR f4r,o -mCN–,H -N,–Rh9-aSloO,2 --ORH4,, -C -C1-6}

3^{-6caylcklyola,l -kOyl-,C -1O-6-aClk3y-l, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, -(C=S)- said -C 6}

1^{-6alkyl is optionally and independently subst cycloalkyl, -Ar1 and–Het1; wherein each of 20 from–halo, -OR35, -NR11R12, -O-C1-6alkyl, and -S-C1-ituted with from 1 to 3 substituents selected R s} _N ^a _R ^{ttached to} _O ^Z _{)-R R} ^m–H,–ha6

5 ⁱ ₁ ^{or Z} ₅ ^{and is selected fro loa,lk -yOl;H, -C} _1-6 ^{alkyl, -O-C} _1-6 ^{alkyl, -S-C} _1-6

6_{R7, -(C= 8, -(C=S)-R8, -SO2-8, -CN, -NR6-SO2-R8, -C3-6cycloalkyl, -O-C3-6c} ^{alkyl, -} a _{tond 3 s–uHbest ycloalkyl, -Ar5 t5i;tu wehnetsre sinele ecatcehd o frfo smai–dh -aClo1-,6a -OlkRyl36 is, - oNpRti2o3nRa2l4l,y - aOn-dC1 in-6daelkpyel,n adnednt -lSy- sCu1b-6satituted with from 1 25 R2 is op stelected from–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each oflk syal;id -C1- andio -nNaRlly13R an14d independently substituted with from 1 to 3 substituents selected from–halo,6a–lOkyRl2 i7s, R3 is op steiolencatlelyd a fnro;}

d_{m ind–eHp,e -nhdaelon,tl -yO sHu,bs -Ctit1u-6taeldky wl,it ahn fdrom -C31-6 tcoyc 3lo saulbkyslt;itu wehnetrein each of said -C1-6alkyl is 30 and -N}

N_{R 8R}

1_{7R18 a1 s selected from–halo,–OR28, R ,r5}

4 _{and R -eR1}

O _e6

-_{Ca;c3-h6cy incdloeapleknyld,e -Cnt3ly-6c syeclleocatlekdyl, fr -oAmr–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - R and R , R 4}

6_{, R7, R9, R10, R11, R12, R13, R14, R15 16, R17, R18 a,n Rd1 -9H, Ret4}

2_{0;, R21, R22, R23, R24, R31, R32, R33, R34 R35 36 are each independently selected from–H, -halo, =O, -OH, -C1-6alkyl, -O-C1-6alkyl,} ^l _-S-C1- ^{35 i 6}

C^{nalkyl, -C3-6cycloalkyl, -Ar6 and–Het6; wherein each of said -C1-6alkyl is optional}

1^{d-6eaplekynld,e -Cnt3l-y6c syucblosatiltkuytel,d -H weitth6, f -rAorm 1 to 3 substituents selected from–halo,–OH, -O-C1-6alkyyl, a -nSd-} R ⁶

a_{nd 8, are each independently} ^{and–NR37R38}

2_{7 and R2} ^;

R₇

3_{-6 Rcy38c,lo aarelk eyla,c -hAr i7nd aenpde–nHdeetn7t;ly s seelleecctteedd f frroomm––HH,, - -Cha1-l6oa,lk -Oyl,H -,C -3C-6}

1_{c-6yacllkoyal,lk -yOl- aCn1d-6a -Hlkeytl2}

3 _,:

-_{C -S-C1-6alkyl,} ^{-6- X1 isN sRe3l-e,c atendd f -rOom-; w–Che1-r6eailnky el-a,c–hO o-Cf1 s-6aaidlky -l-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-6alkyl-, - from 1 to 3 substituents selected fromC1–-h6aallkoy,l- -O isH o,p -tCio1n-6aalllkyyl a,n -dO- iCnd1-e6apleknydl,e -nSt-lyC1 s-6uablskytilt,ut -ed with 5 and -NR33R phenyl, X 34}

2 ^{is NRl-,tdd f -O-; w–Che1-r6eailnky el-a,c–hO o-Cf1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-6alkyl-, - from 1 to 3 substituents selected f sroamid– -Cha1-l6oa,lk -Oyl-H, is -C o1p-6tiaolnkyall,ly -O a-nCd1-6 inadlkeypl,e -nSd-eCn1t-l6yal substituted with -N R32; kyl, -phenyl and 10 Ar1, AR31 beinp A}

g ^{oipitig Ar}

o^{n 16,}

a^{l tlo an 3d}

y ^{an hde A}

i^tr

n^e7

d^{ro a}

e^are

p^{teonm ea}

d^sc

e ^{she ilencdteepden frdoemnt Oly, a N 5 a-nd to S 1;0 e-amcehm obfe sraeidd A arro1,m Aart4i,c A cry5,cl Aer6 o,p atinodna Allry7 OH, -C1-6a ntly substituted with from 1 to 3 substituents selected from–halo, -} a_{nd indepe} ^lk _n ^y _d ^l, _e -_n ^O _tly ^-C _s ^{1-6alkyl, -S-C1-6alkyl, and–NR19R20; wherein each of said -C1-6alkyl is optionally} _{15 Het1, H ubstituted with from 1 to 3 -halo;}

f _Hroemet2

t_{6, 1, H}

a_{n toet}

d _34,

H_{e h H}

t_{ee e}

7_tet5

i_{sr,o H}

o_aptot6

t_iom,

n_{s an}

a_{l sd}

l_{yel H}

a_ence

d_{tte7d ar}

i_{nd fereo e}

p_mac

e_{n Oh}

d_{, in}

e _Nde

n_{tly apne en}

s_dn

u _{Sd; wtlhye are 3in- t eoa 1c0h-m ofe smabider Hedet h1,e Hteerot2c,y Hcelet4 h,a Hveint5g, from–halo, -OH,–C1-6alkyl, bstituted with from 1 to 3 substituents selected each of said -C1-6alkyl is opti -oOn-aClly1-6 aanlkdy iln,d -Se-pCe1n-6daelknytlly, = sOub,s -t}

_{(iCt=tOd)-Ci1th-6a flkyl, 1 an tod 3 -N -Rha21R22; wherein Het8 is a bivalent 3- to 10-membered heterocycle having from 1 t 3 ht t s seleclo;}

2_{0 a wn}

w_{hder Se; ted from O, N in at least one of said heteroatoms is attached to X1 o}

w_heri

s_ehleere

c_{eteinn w}

d _{f sh}

r_ae

o_{imdn R}

– _H1

h_{eat is8–}

l_{o, isH,}

-_{O o t}

H_ph

,_tei–on

C_{n aat}

1_{-l6l lyea}

a_{lk as}

y_nt

l_{,d on}

-_{C ien1d h}

-_6ee

a_pte

l_ker

y_no

l_eda

n_et

e_no

,_{tml -y o}

C_{1 sf}

-_{6u H}

a_be

l_st

k_{t8r yilt i X -us2 Cte a; 3-dtta}

6_{cy wch}

c_ilte

o_hd

a_{l f t}

k_{rooylm X2;}

, _{-C 1 and} ²⁵ _{3-6 tcoyc 3lo saulkbysl,ti -tuOe-nCt1s-} 6 ^{-Cal1k-y6al,lk -ySl-C is1 o-6patlikoynl,a =llyO a, -}

^{(dC i=Od)-pC1-6dalkyl, -C1-6alkyl-O-C1-6alkyl and -NR21R22; wherein each of said Z1 tly substituted with from 1 to 3 -halo;}

A^{1, a Zn2d, Z A3}

2^{, a Zr4e a enadc Zh5 in adreep eeancdhe intdlyp seledctedtly froemle Ccte adnd fro Nm. C and N; and} _{30 M taourtoem iner, p raarctiecmuliacr, m theeta pbroelistee,nt pr ion-v oernt piorendr purgo,v sidaelts, h ayd croamtep,o Nu-noxdid oef fo Fromrm, ourla so Ilava oter t ahe sreteorfe,oisomer,}

_Wherein

^{I -7- R1 isR4 s,e -leScOte2-dR f4r,o -mCN–,H -N,–Rh9-aSloO,2 --ORH4,, -C -C1-6}

3^{-6caylcklyola,l -kOyl-,C -1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, -(C=S)- sai O-C3-6cycloalkyl, -Ar1 and–Het1; wherein each of 5 fromd -–Ch1a-6loa,lkyl is optionally and independently substituted with from 1 to 3 substituents selected R5 is N aRt6tRac7,he -(dC t=o -O}

O ^ZR35

)^{-1R o,}

8^{r -N}

, ^{Z -(5R}

C ^a11

=^nR

S^d12

)^{-R i,s - 8, sOe- -SlCeOc1-t6}

2^ea

-^Rdlky

8 ^f,rlo,

-^{Cm and}

N^{–,H -S}

-^{N,- R–Ch1}

6^-a-6

S^loa

O^,lk

2 ^-y

-^Ol;

R^{8H,, - -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - and–Het5; wherein each of said -C1-6alkyl is optionally and inCd3e-6cycloalkyl, -O-C3-6cycloalkyl, -Ar5 to 3 substituents selected from–halo, -OR36, -NR23R24, -O-C1-6alkpyel,n adnently substituted with from 1} ₁₀ ^R ₂ ^is _op ^s _t ^{elected from–H, -halo, -OH, -C} _1-6 ^{alkyl, and -C} _3-6 ^{cycloalkyl; whereidn - eSa-Cch1-6 oaflk syal;id -C} ₁

a_{ndio -nally and independently substituted with from 1 to 3 substituents selected from–halo-,6} ^a _– ^l _O ^ky _R ^l ₂ ^is

o_ptioeN

n_{cR 7 atle1 , R lyd3}

3 _{is sel R}

a _f1

n_r4o;

d_{m ind–eHp,e -nhdaelon,tl -yO sHu,bs -Ctit1u-6taeldky wl,it ahn fdrom -C31-6 tcoyc 3lo saulbkyslt;itu wehnetrse sinel eeactcehd o frfo smai–dh -aClo1-,6a–lkyl is 15 and -N}

N_{R 8R OR28, R 17R18 a1}

,_r5

4 _{and R -eR1}

C _e6

3_-a;

6_{ccyhcl ionadlekpyle,n -Ode-Cnt3ly-6c syelected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - R6, R7, R9, R10, R11, R12, R13 cloalkyl, -Ar4 and -Het4;}

a_{nd R are each indepe,n Rd1e4n,t Rly15 s,e Rle1c6t,e Rd17 fr,o Rm18–,H R,19 -,h Ral2o0,, = RO21,, - RO2H2,, R -C23}

1_{,-6 Ra2lk4,yl R,3 -1O,- RC32}

1_{-,6a Rlk33yl R,3 -4 36 S,- RC35}

1-^{20 6}

C ^{inadlkeypl,en -dCe3n-6tclyyc sluobaslktiytul,te -dA wr6ith an frdom– 1He tot63; s wuhbesrtietuinen etsac shele octfed sa friodm -–Ch1a-6laol,ky–lOH is, - oOp-tCio1n-6ally and 1-6alkyl, alkyl, -S- R7 and R2 -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38}

2 ^;

R ⁸

7 ^{and R38,, a arree e eaacchh i innddependently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2}

3 ^{: 25 -C3-6cycloalkyl, -Ar7 ependently selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, X is N sRe3l-e,c atendd f -rOom-; w–Che1- a}

r^6ean

i^ld

n^ky–

e^lH-a,e

c^–t7

1 ^hO;

o^{-Cf1 s-6aaidlky -Cl-,1-–6aSlk-Cyl1--6 iaslk oypl-t,io -nCa1l-6lyalk aynld-N iRnd3-eCp1e-6nadlkeynlt-l,y -N suRb3s-Ctit1-6alkyl-, - from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl,ut -epdhe wnith and -NR33 yl,} ₃₀ ^{X R34}

2 ^is _N ^s

f_roR ^e

m₂ ^l-^e _, ^c

1 _a ^te

t_n ^d

o_d ^f

3 _- ^r

s_O ^om

u_{-b;s w} ^–C

t_ithue ^1- e_r ⁶

n_e ^a

t_i ^l

s_n ^ky

s _e ^l- e_a ^,

l_ec ^–

c_h ^O

t_{e o} ^-C

d_f ¹

f _s ^-6

r_oa ^a

m_id ^lky

– _-C ^l-,

h_a1- ^–

l_6oa ^S

,_lk ^-C

-_Oyl ¹-^-6

H_{, i} ^a _s ^lk

-_{C o} ^y

1_p ^l- -_6t ^, _iao - l_n ^C

k_ya ¹⁶

l_l- ,_ly ^alk

-_{O a} ^y

-_n ^l

C_d ^-N

1_{-6 i} ^R _nad ^3- l_ke ^C

y_p ¹

l_,e ^-6

-_n ^a

S_d ^lk

-_e ^y

C_n ^l

1_t- -_l ^,

6_y ^-N

a_{l sku} ^R

y_lb ²

,_s ^-C _tit ¹ _u ^-6 _t ^a _e ^l _d ^ky _w ^l- _i ^, _th - - _{-phenyl and Ar ANrR31}

4_{, ARr32}

1_{, 5,; Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle op 35 comprising 1 to 3 heteroatoms selected from O tionally b OeHin,g - oCp , N and S; each of said Ar1, Ar4, Ar5, Ar6, and Ar7 1t-6ioanlkayllly and independently substituted with from 1 to 3 substituents selected from–halo, - optionally and i,nd -Oep-Cen1-d6aelnktyl, -S-C1-6alkyl, and–NR19R20; wherein each of said -C1-6alkyl is Het1 f,ro Hmet21, H toet 34, h Heetet5r,o Haetot6m,s an sdly}

e_{l H s}

e_ceu

t_tb

e_7s

d _atrit

f_eut

r_{o ee}

m_{adc w}

O_hi

, _itnh

N_{d fero}

a_pm

n_{edn 1 to}

S_{de;n wt 3lhy - e aha}

r_{e 3l;}

i_{n-o t eoa 1c0h-m ofe smabider Hedet h1,e Hteerot2c,y Hcele having 40 Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents ste4,le Hcetet5d,} ^{-8- f eraocmh– ohfa slaoi,d -O -CH1-,6a–lCky1-l6a islk oypl,ti -oOn-aClly1-6 aanlkdy iln,d -Se-C1-6alkyl, =O, -}

^{(C=O)-C1-6alkyl, and -NR21R22; wherein} H_{et8 is a 3- to 1} ^{pendently substittd ith f 1 to 3 -halo;} 5 _{wherein sa0id-m Heemt8be isred op hteiotenraollcyyc alend ha ivnidneg from 1 to 3 het t l td from O, N and S; selected from–halo, -OH,–C1-6alkyl, -C1-6aplkeynledneen,tl -yC1 s-6uablsktyilt-uCte3-d6cy wciltohal fkroylm, -C 13-6 tcoyc 3lo saulkbysl,ti -tuOe-nCt1s-} 6 ^{-Cal1k-y6al,lk -ySl-C is1 o-6patlikoynl,a =llyO a, -}

^{(dC i=Od)-pC1-6dalkytlly, - sCu1-6alkyl-O-C1-6alkyl and -NR21R22; wherein each of said wherein when R1 is–H bstituted with from 1 to 3 -halo; 10 Z , Z4 and Z5 are eac,h th indepte lndetntly s heeletectreodat foromm o Cf H aentd8 i Ns. attached to X2}

1^{, Z2, Z3}

M ^{taourtoem iner, p raarctiecmuliacr, m theeta pbroelistee,nt pr ion-v oernt piorendr purgo,v sidaelts, h ay compound of Formula Ia or a stereoisomer, R1 is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-drate, N-oxide form, or solvate thereof, wherein 15 R 6}

4^{, -SO2-R4, -CN, -NR9-SO2-R4, -C3-6cycloalkyl, alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, -(C=S)- s fraoimd -–Ch1a-6loa,lk -yOlR is35 o,p -NtioRn1a1Rlly12, a -nOd-C in1d-6eaplkeynld, aenndtly -S s - -uO-C3-6cycloalkyl, -Ar1 and–Het1; wherein each of Cbstituted with from 1 to 3 substituents selected R is} _N ^a _R ^{ttached to Z} _R ^o _C ^m _N ^– _, ^H _-N ^, _R ^–h1a-6

5 ^{1 or Z5 and is selected fr loa,lk -yOl;H, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6}

6_{R7, -(C=O)-8, -(C=S)-R8, -SO2-R8, - 6-SO2-R8, -C3-6cycloalkyl, -O-C3-6cycloa} ^{alkyl, -} 0 _{and–Het5; wherein each of said -C1-6alkyl is optionally and independently substituted witlhkyl, -Ar5 2 R2 is to 3 substituents selected from–halo, -OR36, -NR23R24, -O-C1-6alkyl, and -S-C1-6alkyl; from 1 op stelected from–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl,; wherein each of said -C1-6alkyl is andio -nNaRlly and independently substituted with from 1 to 3 substituents selected from–halo,–OR27, 25 R i osp stieolneaclt1}

l_e3

3 _ydR1

a_{n f4}

d_{r;o imnde–pHe,n -dheanlotly, s -OubHs,tit -uCte1-d6a wlkiythl, fr -oCm3-61cy tcolo 3al skuybl;st wituheenretsin se elaecchted of fro smaid–h -aCl1o-6,a–lkOyRl2 i8s, R a a}

N_nn

R_{dd R1}

1 _{R -N}

7_R18,r5

-_eR1

C _e6

4 _{8 a 3-a;}

6_{ccyhcl ionadlekpyle,n -Ode-Cnt3ly-6 selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - 30 R R R cycloalkyl, -Ar4 and -Het4}

6_{, 7, R9, 10, R11, R12 ;}

a_{nd R , R13, Rd1e4n,t Rly15 s,e Rle1c6,te Rd17 f,ro Rm18,– RH1,9 -,h Ra2lo0,, R =2O1,, R -O22H,, R -2C3,1- R24}

6_{alk,y Rl,3 -1O, R-C32}

1_{,-6 Ra3lk3,yl R,3 -4S,- RC35 36 are each indepen 1-} 6 ^{inadlkeypl,en -dCe3n-6tclyyc sluobaslktiytul,te -dA wr6ith an frdom–Het6; wherein each of said -C1-6alkyl is optionally and C 1 to 3 substituents selected from–halo,–OH, -O-C1-6}

1^{-6alkyl, -C3-6cycloalkyl, -Het6, -A alkyl, -S-} ₃₅ ^R _R ⁸

3_{7 and R38} ^, _, ^a _a ^r _r ^e _e ^e _e ^a _a ^c _c ^h _h ⁱ _i ⁿ _n ^d _d ^e _e ^p _p ^e _e ⁿ _n ^d _d ^e _e ⁿ _n ^t _t ^l _l ^y _y ^sr

s^e6

e^l _l ^{e a}

e^cn

c^td

t^e _e ^d–N

d ^f _f ^rR

r^o _o ^m37R

m^–3

–^H8

2^{7 and R2 ;}

H^, _, - -^C _ha ^1- _l ⁶ _o ^a _, ^lk _-O ^yl, _H -_, ^C -³ _C ^-6

1^c _-6 ^y _a ^c _l ^l _k ^o _y ^a _l, ^lk -^y _O ^l- ^a _C ⁿ ₁ ^d _-6a ^-H _lk ^e _y ^t _l ² _, ^: _{-S- s -C s3e-6lecycctelo C1-6alkyl, X da flkroyml, -A–Cr7}

1_{- a6anldky–lH-,e–t7}

1 _{i O;-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-6 40 sN}

N _sR

R_{e3 alkyl-, - X2 i l-e acntedd– fOro-m;–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2}

2_{-, and -O-; -C1-6alkyl-, -NR2-C1-6alkyl-, -} ^{-9- Ar1, c Aorm4,p Arisr5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally being opintigon 1al tloy 3 an hde itnedroeatoms selected from O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and Ar7 5 OH, -C1-6alkyl, -O-C1-6alkpyel,nd -ently substituted with from 1 to 3 substituents selected from–halo, - Het1 and independently substitutedS w-Cith1-6 falkyl,–NR19R20; wherein each of said -C1-6alkyl is optionally f,ro Hmet21, H toet 34, h Heetet5r,o Haetot6m,s an sdel Hecette7d ar fero}

r^{o em}

m^{ac 1}

O^{h t}

, ^{ion Nd 3e - aph}

n^ea

d^nlo

S^{d;ently a 3- to 10-membered heterocycle having} H_{et6, and} ^{; wherein each of said Het} ₁ ^{, Het} ₂ ^{, Het} ₄ ^{, Het} ₅ ^, _{10 from–halo H,e -Ot7H is,– oCp1tionally and independently substituted with from 1 to 3 substituents selected Het}

8 _{e iasc ah 3 o-f t soa 1id0- -mC -6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -(C=O)-C1-6}

1_{e-6mablkey alkyl, and -NR21R22; wherein rle isd o hpettieornoaclylycl aen hda ivnidependently substittd ith f 1 to 3 -halo;}

w_{herein said Het8 is optionally and indnegp feronmde 1nt tloy 3 su hbesttitutetd withl frotmd 1 from O, N and S; selected from–halo, -OH,–C1-6alkyl, -C1-6alkylene, -C1-6alkyl-C3-6cycloalkyl, -C3-6 tcoyc 3lo saulkbysl,ti -tuOe-nCt1s-} ^{15 - 6alkyl, -S-Cs1-6alkyl, =O, -}

^{(C=O)-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and -NR21R22;}

w^{Ch1e-6raeliknyl w ihe onpt Rionally ad idp d tly substituted with from 1 to 3 -halo; wherein each of said Z 1 is–H, th t l t heteroatom of Het8 is attached to X2}

1^{, Z2, Z3, Z4 and Z5 are each independently selected from C and N. 20 I tn}

R^{a1u at io further embodiment, the present invention provides a compound of Formula Ia or a stereoisomer, sm seerle,c ratecdem friocm, m–eHta,b–ohlaitelo,, p -rOo-H o,r -C pr1e-6darlukgyl,, s -aOlt-,C h1y-6darlaktyel,, N -S--oCx1id-6eal fkoyrlm, -,N oRr s9Rol1v0ate thereof, wherein R4, - , -(C=O)-R4, -(C=S)- saidS -CO2}

1^{--6R4, -CN, -NR9-SO2-R4, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; wherein each of 25 from–haloa,lk -yOlR is35 o,ptionally and independently substituted with from 1 to 3 substituents selected R5 is N aRttached t=oO Z)-1R or -N Z5R a11nRd12 i,s - sOe-lCec1-t6eadlky frlo,m and–H -S,-–Ch1a-6loa,lk -yOl;H, -C1-6}

6^{R7, -(C 8, -(C=S)-R8, -SO2-R8, -CN, -NR6-SO2-R8, -C3-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -} a_{nd–Het5; wherein each of said -C1-6alkyl is optionally and indep} ^c _e ^y _n ^cl _d ^{oalkyl, -O-C3-6cycloalkyl, -Ar5} t_{o 3 substituents selected from–halo, -OR36, -NR23R24, -O-C1-6alkyl, anednt -lSy- substituted with from 1 30 R2 is op steiolencatlelyd a fnrodm ind–eHp,e -nhdaelon,tl -yO sHu,bs -Ctit1u-6taeldky wl,it ahn fdrom -C31-6 tcoyc 3lo saulbkyslt;itu wehnetrse sinel eeaC}

c_tceh1-6

d _oa

f_rflk

o _sy

m_{al;i–dh -aClo1-,6a–lOkyRl2 i7s, R s an}

o_{p sd}

t_{eiol -eN}

n_cR

a_tle1

l_yd3R

a _f1

n_r4

3 _{i o;}

d_{m ind–eHp,e -nhdaelon,tl -yO sHu,bs -Ctit1u-6taeldky wl,it ahn fdrom -C31-6 tcoyc 3lo saulbkyslt;itu wehnetrse sinel eeactcehd o frfo smai–dh -aClo1-,6a–lOkyRl is 35 and -NR 28 i ,1 R5 , R, R7, R9 R16}

6 _{10,; R11, R12, R13, R14, R15, R16, R19, R20, R21, R22, R31, R32, R33 and R34 are each Anrd6e apnedn–dHenettl6y; w sehleerceteind e farocmh o–fH s,a -idha -lCo1,-6 =aOlk,y -lO isH o,p -tCio1n-6aalllkyy al,n -dO i-nCd1e-6paelknydle,n -Stly-C s1u-6baslktiytul,te -Cd3 w-6icthyc flrooamlkyl, - 3NR s3ubstituents selected from–halo,–OH, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het6, -Ar6 an 1d to– 40 R 7}

2_{7 aRnd38 R;28, are each independently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2:} ^{-10- R37 a -Cnd3-6 Rcy38c,lo aarelk eyla,c -hAr i7nd aenpde–nHdeetn7tly selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, X1 is}

5 ^{N sRe3l-e,c atendd f -rOom-; w–Che1-r6eailnky el-a,c–hO;}

o^-C

e^{f1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-6alkyl-, - from 1 to 3 substituents selectd sa friodm -C1–-h6aallkoy,l- -O isH o,p -tCio1n-6aalllkyyl a,n -dO- iCnd1-e6apleknydl,e -nSt-lyC1 s-6uablskytilt,ut -epdhe wniythl, X and -NR33R34}

2 ^{isN sRe2l-e,c atendd f -rOom-; w–Che1-r6eailnky el-a,c–hO o-Cf1 s-6aaidlky -Cl-,1-–6aSlk-Cyl1--6 iaslk oypl-t,io -nCa1l-6lyalk aynld-N iRnd3-eCp1e-6nadlkeynlt-l,y -N suRb2s-Ctit1u-6talkyl-, - from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl ed with 10 Ar1, - c AN}

o^rR31

m^{4,p AR}

r^isr32

5^{in,; , -phenyl and g Ar 16, to an 3d he Atre7ro aaretom easc she ilnedcteepden frdoemnt Oly, a N 5 a-nd to S 1;0 e-amcehm obfe sraeidd A arro1,m Aart4i,c cycle optionally being optionally and independently substituted with from 1 to 3 substituents sel Ar5, Ar6, and Ar7} O_{H, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19R20; wherein each of} ^e _s ^c _a ^te _i ^{d from–halo, -} _{15 Het1 o,p Htieotn2,a Hllyet and independently substituted with from 1 to 3 -halo; d -C1-6alkyl is from 1 to 34, h Heett5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having Het6, and Het7e isro oaptotims selected from O, N and S; wherein each of said Het1, Het2, Het4, Het5, from–halo, -OH,–C1-o6nally and independently substituted with from 1 to 3 substituents selected 20 Het each of said -C1-6 alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

_{(C=O)-C1-6alkyl, and -NR21R22; wherein}

8 _{is a 3- to 10-meamlkbyelr iesd o hpetiotenraolclyyc alned h ianvdienpge fnrodmen 1tly to su 3bs htitttdtith f lc 1te tod 3 fr -ohmalo O;, N and S; werin}

5 _{whhereein a wt}

2 _{h leenas Rt1 o inse– oHf, s tahiedn h aette leroaatto omnes i hse atettraocahtoemd t oof X H1e otr X2}

8 _{is a;}

w _{ttached to}

s_{ehle s}

e_{r X2; and}

c_{eteind f sraoimd– Hheat8lo, is -O oHp,ti–oCna1-l6lyalk aynl,d -C in1d-6eaplkeynledneen,tl -yC1 s-6uablsktyilt-uCte3-d6cy wciltohal fkroylm, -C 13-6 tcoyc 3lo saulkbysl,ti -tuOe-nCt1s-} 6 ^{-Cal1k-y6al,lk -ySl-C is1 o-6patlikoynl,a =llyO a, -}

^{(dC i=Od)-pC1-6dalkyl, -C1-6alkyl-O-C1-6alkyl and -NR21R22; wherein each of said 0 Z1, Z2, Z3, Z4 and Z5 are each idp d tltyly seulebcstteitdut ferdom wi Cth a frnodm N 1. to 3 -halo;}

3 ^{In a a fu srttheerero eimsobmoedrim, teanutt,o tmheer p,re rasceenmt iincv,e mnetiotanbo plriotev,id perso a compound of Formula Ia or of Formula I or solvate thereof, wherein each of said Z1, Z2, Z3, Z4 a-n or predrug, salt, hydrate, N-oxide form, or} a_{nd p} ^{d Z5 is C; and wherein the further definitions} _{35 rovisions as defined herein above apply.}

I_{n a t fauurtther embodiment, the present invention provides a compound of Formula Ia or a stereoisomer, wheomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, s aebloer}

v_ce

e_tein

a_{d s farid Het8 is a saturated 3- to 10-membered heterocycle having from 1 to 3 heteroatoms 40 pploym. O, N and S; and wherein the further definitions and provisions as defined herein} ^{-11- I tnau ato fmurethr,e rra ecmbodiment, the present invention provides a compound of Formula I or a stereoisomer, whe emic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, 5 R A1 ar}

i^snedin

e ^{Al2 aered e fach indepen}

R¹

5 ^{is s seleecctted frroomm––HH, a -nhda–dheanltoly; selected from C and N;} R_{2 is selec} ^{lo and -C1-6alkyl;}

R_{3 is selectteedd f frroomm––HH a anndd - -CC1-6}

1_{-6aalkyl; 10 X X1 is selected from–O-C1-6alkyl-, -lNkyRl;3-C1-6alkyl- H2et is8 s isele act 3e-d t foro 1m0- -mC1e-6mablkyl-,–O-C1-6alkyl-, -NR,2 --NCR3}

1_{-6-a,l -kOyl--;, -NR2-, -O-;}

s_{ubstituents selectede frreodm he–thearlooc,yc -OleH;, wh–eCr1e-6inalk syal,id -C H1e-6ta8lk isyle onpeti,on -aCll3y-6c syucblosatiltkuytel,d -C w1it-6hal 1ky tl-oC 33-} Z ⁶

1^{, Z2c,y Zcl3o,a Zl4ky aln,d -}

^{(C Z=O)-C1-6ahlkyl, and -(C=O)-C3-6cycloalkyl ; and}

1^{5 C}

I ^{tnau ato fmurethr,e rra ecmemboicd,i mmeetnatb,o thliete p,r persoe-n otr i pnrveedntion provides a compound of Formula I or a stereoisomer, wher rug, salt, hydrate, N-oxide form, or solvate thereof, 20 A R1}

R^{1 a isne}

s^{din A2 aered e frach independently selected from C and N;}

5 _{is s} ^e _e ^l _l ^e _e ^c _c ^t _{ted fr} ^o _o ^m _m ^– _– ^H _H, ^a -ⁿ _h ^d _al ^–halo;

R_{2 is selec o and -C1-6alkyl;}

R_{3 ted from–H and -C1-6alkyl;}

X_{1 i iss s seelleecctteedd f frroomm––OH-C and -C1-6,a -lkyl;}

2_{5 X 1-6 -C}

H_{2et is8 s -NNRR3}

2_-C1-6

1_{-6aallkkyyll--,, - -NNRR3}

2_{--,, - -OO- su iselected from–O-C1-6aallkkyyll--, -;}

- _;

b_{s atit 3uen tots 1 s0e-lemcetemdb ferroemd– hheateloro,c -OycHle,;– wCh1-e6arelkinyl, s -aCid1-6 Halekty8le inse o,p -Ctio3-n6cayllcylo saulkbyslt,itu atnedd -C w1it-6hal 1ky tl-oC 33-} ^{30 Z 6}

1^{, Z2c,y Zcl3o,a Zl4ky aln;d an Zd5 are each C.}

I _t ⁿ _a1u ^a

i_tso ^f _m ^ur

N_e ^{ther embodiment, the present invention provides a compound of Formula I or a stereoisomer,} A _{arn,d ra Ace2m isic C,. metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein 35} ^{-12- I} _t ⁿ _au ^a _to ^f _m ^ur _e ^th _r, ^e _r ^r _a ^e _c ^m _em ^bo _ic ^d _, ^im _m ^e _e ⁿ _ta ^t, _b ^t _o ^h _l ^e _ite ^p _, ^r _p ^e _r ^s _o ^e-ⁿ _o ^t _r ⁱⁿ _p ^v _re ^e _d ⁿ _r ^ti _u ^o _g ⁿ _, ^p _sa ^ro _lt ^v _, ^id _h ^e _yd ^s _r ^a _ate ^co _, ^m _N- ^p _o ^o _x ^u _id ⁿ _e ^d _f ^o _o ^f _rm ^Fo _, ^r _o ^m _r ^u _s ^l _o ^a _lv ^I _a ^a _te ^or _th ^a _e ^s _re ^te _o ^r _f ^eoisomer,

^{5 Whe}

^{I R R1 i isr}

s ^{seeinlected from–H and–}

R⁵

2 ^{is a settlaecchteedd f troom Z1– aHnd an is sehleaclote;d from–H and -C1-6alkyl;}

R^{3 is selected fr d -C1-6alkyl; 10 X1 is selected froomm––OH- aCn 1- 1d-6a -Clkyl6-a,l -kNyl;}

X^{2 -O-;}

H_et ^is ₈ ^{selected from–O-C1-6alky R3-C1-6alkyl-, -NR3-,} 1 _{is t 0}

-_{o a}

C _{33 s-u tobs 1titu-menetm}

-_{sb seerleecdte Nd-} ^l- _c ^,

f_o - r_on ^N

m_t ^R _ai ²

–_n- h_i ^C _n ¹

a_g ^-6

l_{o h} ^a

,_e ^lk

-_Ot ^y _e ^l

H_r-_o ^,

,_c ^-N

–_yCc ^R _l1e ^2- -_6; ^,

a _w ^-O

l_khye ^-;

l_{,re -Cin1- s6aalikdy Hleente8, is -C o3p-6tcioyncalolalylk syul,b -sOtit-uCted with -S}

_{(C=O)-C 1-6 1-6alkyl, =O, 1-6alkyl, -C1-6alk alkyl, Z1, Z2, Z3, yl-O-C1-6alkyl and -NR21R22 ; and}

1_{5 Z4 and Z5 a h C}

M_{ore in particular the present invention provides a compound selected from the list comprising:}

_C

_{p d N1 E pl N1 C p d N2 E pl N2} ^-13- _C

_{p d N3 E pl N3 Cp d N4 E pl N4 Cp d N5 E pl N5 Cp d N6 E pl N6 C}

_{p d N7 E pl N7 Cp d N8 E pl N8 C}

_{p d N9 E pl N9 Cp d N10 E pl N10} ^-14- _C

_{p d N11 E pl N11 Cp d N12 E pl N12 C}

_{p d N13 E pl N13 Cp d N14 E pl N14 C}

_{p d N15 E pl N15} ^{Cp d N16 E pl N16 C}

^{p d N17, E pl N17 Cp d N18, E pl N18 -15-} _C

_{p d N19 E pl N19 Cp d N20 E pl N20 C}

_{p d N21, E pl N21 Cp d N22, E pl N22 C}

_{p d N23 E pl N23 Cp d N24 E pl N24 C}

_{p d N25 E pl N25 Cp d N26 E pl N26} ^-16- _C

_{p d N27 E pl N27 Cp d N28 E pl N28 C}

_{p d N29 E pl N29 Cp d N30 E pl N30 C}

_{p d N31 E pl N31 Cp d N32, Example N32 C}

_{p d N33 E pl N33 Cp d N34 E pl N34} ^-17- _C

_{p d N35 E pl N35 Cp d N36 E ple N36 C}

_{p d N37, E pl N37 Cp d N38, E pl N38 Cp d N39 E pl N39 Cp d N40 E pl N40 C}

_{p d N41, E pl N41 Cp d N42, E pl N42} ^-18- _C

_{p d N43 E pl N43 Cp d N44 E pl N44 C}

_{p d N45 E pl N45 Cp d N46 E pl N46 C}

_{p d N47 E pl N47 Cp d N48 E pl N48 C}

_{p d N49, E pl N49 Cp d N50, E pl N50} ^-19- _C

_{p d N51 E pl N51 Cp d N52 E pl N52 C}

_{p d N53 E pl N53 Cp d N54 E pl N54 C}

_{p d N55, E pl N55 Cp d N56, E pl N56 C}

_{p d N57 E pl N57 Cp d N58 E pl N58} ^-20-

_C

_{p d N59, E pl N59 Cp d N60, E pl N60}

_C

_{p d N61, E pl N61 Cp d N62, E pl N62}

^C _M ^p _{i p} ^d _t ^N _i ⁶³ _l ^E _{th p} ^{pl N6} _t ³ _{i ti pid p dltd f th lit piing:}

_{Cp d N46 E pl N46} ^{Cp d N47 E pl N47 -21-}

_Co

_{p d N48 E pl N48 Cp d N49, E pl N49}

_{Cp d N43 E pl N43 Cp d N45 E pl N45}

_{Cp d N50 E pl N50} ^{Cp d N27 E pl N27}

_C

_{p d N44 E pl N44} ^{Cp d N59, E pl N59 -22-}

C_{op d N60 E pl N60 Cp d N63 E pl N63}

_Comp

_{d N62, E pl N62;d More in particular the present invention provides a compou} ^C _nd ^om _se ^p _l ^o _e ^u _ct ⁿ _e ^d _d ^N _fr ⁴ _o ⁴ _m ^{, E} _th ^x _e ^am _lis ^p _t ^l _c ^e _o ^N _m ⁴ _p ⁴ _rising:

_{Cp d N27 E pl N27} C^{p d N45 E pl N45}

^C

^{p d N43 E pl N43}

^-23-

C

_{p d N59, E pl N59 Cp d N62 E pl N62}

_C

_{p d N60, E pl N60} ^{Cp d N63 E pl N63} _{More in particular the present invention provides a compound selected from the list comprising:}

C^o

^p _a ^d _n ^N _d ^{60, E pl N60}

C_o

_{p d N45 E pl N45} ^{-24- I innv aen futirothne,r w phaerrteicinula Rr5 embodiment, the present invention provides a compound according to this the numbering as prov iisde lidnk ined Fo torm thuela a Iry olr o Iar. heteroaryl moiety at position Z1 in accordance with 5 I tnhis ye intv ae fnutriothne,r w phaerrteiciunla srai edm cboomdiment, the present invention provides a compound according to Inhis ye intv ae fnutriothne,r w phaerrteiciunla srai edm cboomdp}

p^{iound is the S-enantiomer.}

t ^{mouenndt, i tshe the pr Res-eennatn intivoemnetior.n provides a compound according to 10 I ctom ispr aisin fugrth aer co ombjpeoctun odf a thceco prdreinsgen tt invention to provide (pharmaceutical) compositions compositio o this invention. In particular, the compounds and} m_edicine.T ⁿ _h ^s _e ^a _c ^c _o ^c _m ^or _p ^d _o ⁱⁿ _u ^g _nds ^to _a ^t _n ^h _d ^is _c ⁱⁿ _o ^v _m ^e _p ⁿ _o ^ti _s ^o _i ⁿ _tion ^a _s ^re _a ^s _c ^u _c ⁱ _o ^ta _rd ^{ble for use as a human or veterinary} i_{nhibiting the activity of a kinase, in particular LRRK2 kininagse t,o an tdhi msa iynv been utiosend a forer th seuitable for 15 a dnisde/aosre. prevention of neurological disorders such as Alzheimer’s disease or Pa trrekiantsmoenn’st}

_{I onf a a f nineaulr ooblojegcictiavle d,i tshoerd perer,se suncth inv aesn Atioln provides a method for the prevention and/or treatment 20 c toom thpisri isninvegn atidomn.inistering to a subject iznh neeimeedr’ tshe driesoefa ase co omrp Poaurknidns oorn a’s c doimsepaosseit;io snai adc mcoertdhinogd}

_{A talutetornmaetirv,e rlayc,e tmheic, p mreesteanbtol iintev,e pnrtoio-n or p prroevdidruegs, s aal ct,o hmypdorautned, N o-fox Fiodrem fourlam, I o orr so alva stteer tehoeirseoomf,er,}

^{25 Wh}

^I

R^{1 iesrein}

(^{C s=eSle)c-Rted frSoOm–H,–halo, -OH, -C1-6lkyl, -O-C1-6lkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4 4, - 2-R4, -CN, -NR , -} _{30 w suhbesrteitiune enatsch se olefc staeidd f -rC} ⁹

o_{m1-6a–lhkayl}- l_{o i} ^S _s ^O

, _{- o} ²

O_p- R_t ^R _i3o ⁴

5_n ^,

,_a - -_Nl ^C _ly ^3- R _a ^6c

1_1n ^y

R_d ^cl

1_{2 i} ^o

,_n ^a

-_d ^l

O_e ^k

-_p ^y

C_e ^l,

1_n ^{-O-C3-6cycloalkyl, -Ar1 and–Het1;} -_{6daelknytlly, a snudbs -Stit-uCte1-d6a wlkiythl; from 1 to 3} ^-25- R_{5 is attached to Z1 or Z5 and is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- 6^{cycloalkyl, -Ar5 and–Het5; wherein each of said -C1-6alkyl is optionally and independently 5 s}

R^{2 is aunbstituted6 with from 1 to 3 substituents selected from–halo, -OR36, -NR23R24, -O-C1-6alkyl, is sed}

o^{lpe -S}

t^ciot-eC

n^{d1- al flra}

y^olkmyl

a^n–;

d^{H i,n -dheapleo,n -dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanch of said -C1-6alkyl} i _a

1_{0 sh}

i _,14

3 _n

h_{s selo a olpe,} ^{ts selected from–} R _tc–

i_{otOe 7}

n_dR2

a_{l flryo,m an}

a_{n–d R}

d_{H -N}

i_{,n -dh1}

e_a3

p_lR

e_{on -;}

d_{OeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetiitu eeanctsh o sfe sleacidte -dC f1r-o6amlky–l R4 andlo, R–8O aRre28, e aancdh - iNnRde15pRe1n6d;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- 15} ^{R 6}

6^{, Ra7l,ky Rl,9, -N RR17}

1^{0,R R18}

1^{1,, - RC3-6}

1^{2,c Ry1c3l,oa Rlk14y,l, R -1O5,-C R3-6}

1^{6c,y Rc1lo7,alkyl, -Ar4 and -Het4;}

R_{34, R35 and R36 are each independently selec} ^R _te ¹ _d ^8, _f ^R _ro ¹ _m ^{9, R} _–H ²⁰ _, ^, - ^R _ha ²¹ _l ^, _o, ^R ₌ ² _O ^2, _, ^R _-O ²³ _H ^{, R} _{, -} ² _C ^4, _1- ^R31

6_alk ^, _y ^R _l, ³ -² _O ^{, R} _-C ³³

1^,- 6 ^{oapltkioyln,a -llSy- aCn1d-6a inlkdyel,pe -Cnd3-e6cnytlcylo saulbkyslt,itu -tAerd6 w ainthd fr–oHmet 16; t wherein each of said -C1-6alkyl is –OH, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het o 3 substituents selected from–halo,} R _{dently selected from–H, -} ⁶

7 _{and R28 are each indepen C} ^, ₁ --^A _6a ^r6 _lk ^a _y ⁿ _l, ^d _-C ^– ₃ ^N _-6 ^R _cy ³⁷ _c ^R _l ³⁸

2 ^;

2_{0 R37 and R38 are each independently selected from–H, -halo, -OH, -C1-6alkoyall,k -yOl- aCn1d-6 -aHlkeytl2,: -S-C1- X} ⁶

1 _is ^al _s ^k _e ^y _l ^l _e ^, _c ^-C _te ³ _d ^-6c _f ^y _ro ^c _m ^loa _– ^lk _C ^y ₁ ^l, _-6 -_a ^A _lk ^r7 _yl ^a _-, ^nd _–O ^–-^H _C ^e ₁ ^t7

-₆ ^; _{alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3} 6^a _-C1- s^{ulbksytl-it,ut -eNdR w3-i,th a fnrdom -O 1-; to wherein each of said -C1-6alkyl- is optionally and independently} _{25 X2 isS- sCe1l-e6acltkeydl, f -rpohmen–yCl,1 a} ^{3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -} -_{6nadlk -yNl-R,3–3RO3-4C;1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} 6 ^{saulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C fr1o-6malk–yhl-al ios, o -OptHio,n -aCll1y-6a alknyd independently 30 S-C1-6alkyl, -phenyl and -N l, -O-C1-6alkyl, - Ar, o Aprti4o,n Aalrl5y, c Aorm6,pr aisnidng A 1r7 to aR}

3^re31R

h^{e e3}

t^a2

1 ^ec;

r^{hoa itnodmespe snedleecntetlyd a 5- to 10-membered aromatic cycle Ar5, Ar6, and Ar7 being optionally and indepen frdoemntl Oy, s Nub asntdit S; each of said Ar1, Ar4,} s_{ubstituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S} ^u _-C ^te ₁ ^d _-6a ^{with from 1 to 3} w_{herein each of said -C1-6alkyl is optionally and independently substitutlkyl, and–NR19R20; 35 Het1h}

h_,a

a _Hlo

v_{e; ed with from 1 to 3 - int2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro inmde Op,e Nnd aenndtly S a; w 3h-e tore 1in0- emaechmb oefr seadid h Heterocycle Het4, Het5, Het6, and Het7 is optionally and independently substituted with fromet11, H toet23,} ^{-26- 6} _s ^a _{ubstituents selected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

_(C=O)-C1- s^{ulkyl, and -NR21R22; wherein each of said -C1-6alkyl is optionally and ind} 5 _a ^isb

d ^asti

S ^3tu

;^{-te tod 1 w0it p d tly Het8 -hm ferommbe 1re tod 3 he -htearloo;cycle having from 1 to 3 heteroatoms selected from O, N} w_n

s_{ehleerceteind s faroidm H–eht8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om -}

_{(C 1=O to)- 3C s1-u6ablsktyitlu,e} 6 _-nCt1s- i^{nadlkeypl-eOn-dCe1n-6talylk syulbs atnitdute -dN wRi2th1R fr2o2;m w 1h toer 3ei -nha each of said -C1-6alkyl i pti lly and 10 Z wherein when R1–H, then at least one heteroalot;om of Het8 is attached to X2}

A¹

1^{, a Zn2d, Z A3}

2^{, a Zr4e a enadc Zh5 in adreep eeancdhe inntdlyep seenledently selected from C and N; and}

I ^{tnau ptoamrteicru,la rar,ce tmheic, p mreesteanbtol iintev,en ptrioo-n o pc}

r^rte

p^{orvdd f}

e^idero

r^usm

g^{, a C}

s^{a c a}

l^on

t^,md

h^{p N}

y^odu.

r^{antde, o Nf- Foxoirdmeu fla I or a stereoisomer,} _{15 w} ^{orm, or solvate thereo} R_{h1e isre}

(_{C sin} ^f, =_{eSle)c-Rte4d, - frSoOm2-–RH4,, -–ChNal,o, -N -ORH9-,S -OC1-6}

2_{-Ra4l,ky -Cl,3 --O6-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - wherein each of said -C1-6alkyl is optio cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; 20 substituents selected from–halo, -O nally a11nRd12 i,n -dOe-pCe1n-6daelknytlly, a snudbs -Stit-uCte1-d6a wlkiythl; from 1 to 3 R5 is 6}a _alk_tty_al_c,_he -S_d- _tC_{o1- Z1}

6al _oky_rl _Z,₅ - _aN_nR_{d6 i}R_{s7 s},_el -_e(C_ct=_eO_dR

) _f3

-_{r5, -NR}

R_om8,_– -_H(C_,=_–S_ha)-_lR_o,8, _-O -_HS_,O _-2C-R_1-6

8_a,_lk -_yC_l,N -,_OH -N_,R _-C1-6

6-S_aO_lk2-_yR_{l,8 - -C} o ,_O -C_{1- 3-} 6 ^{acnydcl inadlkeyple,n -dOe-nCt3ly-6c syucblosatilkyl, -Ar5 and–Het5; wherein each of said -C1-6alkyl is optionally NR23R24, -O-C1-6alkyl, antuted with from 1 to 3 substituents selected from–halo, -OR36, - 25 R2 is is se olpetciotendal flryom an–dH i,n -dheapleod, - - ndOS}

e^H-C

n^t,1

l^{y --C6a}

s^1u-l6k

b^ay

s^llk;

t^{iytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; wherein each of said -C1-6alkyl} h_{alo,–OR27, a} ^{3 substituents selected from–} R _s

0 _{is se olpetciotendal flryomn}

a_n–d

d_{H -N}

i_{,n -R}

d_h1a3lRo,14

3 _{i -;OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl 3 R ahnadlo, R–OR28, ancdh - iNnRe}

d_{e1p5endently substituted with from 1 to 3 substituents selected from– 4 8 are ea pRe1n6d;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R ^{R 6a} ₇ ^{l,k Ryl} ₉ ^{,, - RN} ₁ ^R17

0^{, RR18}

1₁ ^{,, R -C3-6}

1₂ ^{, Rc} ₁ ^y ₃ ^{c,lo Ra} ₁₄ ^{lk,y Rl,} ₁ -₅ ^{O, R-C3-6}

1₆ ^{, Rcy} ₁₇ ^{c,lo Ra} ₁ ^l ₈ ^{k,y Rl,} ₁ -₉ ^{A, Rr4}

2 ^a ₀ ^{,n Rd} ₂ -₁ ^{H,e Rt4}

6^, ₂₂ ^{;, R} ₂₃ ^{, R} ₂₄ ^{, R} ₃₁ ^{, R} ₃₂ ^{, R} ₃₃ ³⁵ _{R35 and R36 are each independently s} ^r _{elected from–H, -halo, =O, -OH, -C1-6alkyl, -O} ^R _-C34

- ₁ ^,- 6 _o ^a _p ^l _t ^k

H_io ^yl

,_n ^,

-_aOll ^S _y- -_{C a} ^C

1_n ¹

-_6d ^-6a

a_{lk in} ^lk

y_d ^y

l_,e ^l,

-_pSe ^-C

-_nCd ^3- 1_e ^6c

-_6n ^y

a_tlkl ^c _y ^lo

y_{l s} ^a

,_u ^l

-_Cb ^ky _s ^l

3_t ^,

-_6itcu - y_t ^A

c_eld ⁶

o_{a w} ^a

l_ki ⁿ _tyh ^d

l_{, f -r} ^–

H_o ^H _m ^et

e_t61 ^6;

, _{- tAo} ^w

r₆₃ ^he

a _s ^r

n_u ^e

d_b ⁱⁿ _s–tNit ^e _u ^a

R_e ^c

3_n ^h

7_Rts ^o

3_{8 s} ^f

;_ele ^sa _ct ^id _ed - _f ^C _ro ^1- _m ^6al _– ^k _h ^y _a ^l _lo ^is –_{O ,} ^{-27- R R27 and R28}

3^{8,, a arree e eaacchh in inddeeppeennddeenntlytly se sleelcetcetded fro frmom–H–,H -,C -1h-6aallok,y -l,O -CH3,-6 -cCy1c-6laolalkyl and -Het2 37 and R :} C_{1-6alkyl, -C3-} 5 _o6c ^{kyl, -O-C1-6alkyl, -S-} X_{1 is selected frmyc–loCa1lk-6yall,k -yAl-r,7– aOnd-C–1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} X ⁶

A^{2r isa sleklyelc-,te adnd fro -NmR- ,–3}

a^O;

n^{-dC2 A-3ralkyl-,–S-C2-3alkyl-, -NR2-C2-3}

1^{, Ar4, Ar5, Ar6 7 are each independently aalk 5y-l-, to -N 1R02--m, aend -O-;}

o^{ptionally comprising 1 to 3 heteroatoms selected from O, N and Smbered aromatic cycle Ar5, Ar6, and Ar7 being optionally and independently substitute; each of said Ar1, Ar4, 10 s} _w ^u _h ^b _e ^s _r ^t _e ^it _i ^u _n ^e _e ⁿ _a ^ts _ch ^se _o ^l _f ^e _s ^c _a ^te _id ^d - ^f _C ^ro _1- ^m _6al ^– _ky ^h _l ^a _i ^l _s ^o, _o -_p ^O _tio ^H _n ^, _a -_l ^C _ly ^1- _a ^6a _n ^l _d ^ky _in ^l, _d -_e ^O _p-_e ^{C1-6alkyl, -S-C1d-6al wkyitlh, a fnrodm–N 1R1 t9oR203;}

h_{alo; ndently substituted with from 1 to 3 - Het1 h,a Hveint2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeach independently a 3- to 10-membered heterocycle 15 H suebt4s,tit Hueetn5t,s H seetl6e,ct aendd fr Homet7– ihsal oop,t -ionalldy fr aonmd O in,d Nep aenndde Sn;t wlyh seurebisnti etuatcehd o wfi sthaid fro Hmet11, H toet23,} 6^a _{OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

_(C=O)-C1- s^{ulbksytl,itu atendd w -iNthR f2r1oRm221; t woh 3er -ehin each of said -C1-6alkyl is optionally and indp d tly} ₂₀ ^Het8 _a ⁱ _n ^{s a 3- to 10-membered hetearloo;cycle having from 1 to 3 heteroatoms selected fro}

w _sehd

l_{eer S}

c_e; ^{m O, N} t_{eind s faroidm H–eht8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om -}

_{(C 1=O to)- 3C s1-u6ablsktyitlu,e -nCt1s-} 6^{alkyl-O-C1-6alkyl and -NR21R22; wherein each of said}

2^{5 independently sub h -C1-6alkyl i pti lly and Z wherein when R1 isst–itHut,e tdhe wnit at fr leoamst 1 o tnoe 3 h -ehtaelroo;atom of Het8 is attached to X2}

A¹

1^{, a Zn2d, Z A3}

2^{, a Zr4e a enadc Zh5 in adreep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and}

_{30 t} ^{More in particular the present invention provides a compound of Formula I or a}

w_{automer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or so} ^s _lv ^te _a ^r _t ^e _e ^o _t ⁱ _h ^so _e ^m _re ^e _o ^r _f ^, _{, Rh1e isre}

(_{C sin}

=_e,

S_{le)c-Rte4d, - frSoOm2-–RH4,, -–ChNal,o, -N -ORH9-,S -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - wherein each of said -C1- O2-R4, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; 35 R5 is su abtstatictuhe}

N_endts

R _{t sel1ected from6a–lhkayllo is, - oOpRti3o5n,a -NllyR a11nRd12 i,n -dOe-pCe1n-6daelknytlly, a snudbs -Stit-uCte1-d6a wlkiythl; from 1 to 3 6}R_{o7 Z}, -( _oC_r= _ZO₅)- _aR_n8d, _i -_s(C _s=_eS_le)_c-R_te8d, _f -_rS_oO_m2-_–R_H8,_, -_–C_hN_al,_o -_,N _-OR_6H-S_,O _-C1-6

2-R_a8,_lky -C_{l,3 --6O}c-y_Ccl₁o_-6a_al_lk_ky_yl_l,_, - -O_S--_CC_{1- 6}alkyl, - _3- ^{-28- 6 scuy y nbcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteitiune enatsch se olefc staeidd f -rCom1-6a–lhkyallo is, - oOpRtio36n,a -lNlyR a23nRd24 in,d -Oep-Cen1-d6aelnktyll 5 s a}

i^{s sed}

o^{lpe -S}

t^ciot-eC6

2 ^{i nd1- , R al flra}

y^olkmyl

a^n–;

d^{H i,n -dheapleo,n -dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeancth of said -C1-6alkyl} 3 _{is ha}

i_{s selo}

o_lpe, ^{s selected from–} R _tc–

i_otOendR27

a_{l flryo,m an}

a_n–d

d_{H -N}

i_{,n -R}

d_h1

e_a3

p_lR

e_o,14

n _-;

d_{OeHnt,ly -C s1u-6baslktiytul,te adnd w -C3-6cycloalkyl; wherein each of said -C1-6alkyl 10 halo, ith from 1 to 3 substituents selected from– R and} ^y _R–

l^, _8O

-^N _aR

R_{re28, e aancdh - iNnRde15pRe1n6}

4 _{d;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6}

6^{alk 17R18, -O-C3-6cy} _{alkyl, -S-C1-} R ^R ₇ ^{, R} ₉ ^{, R} ₁₀ ^{, R} ₁₁ ^{, R} ₁₂ ^{, R} ₁₃ ^{, Rc} ₁ ^l ₄ ^{o,a Rlk} ₁ ^y ₅ ^{l,, R -C3-6}

1₆ ^{, Rcy} ₁₇ ^{c,lo Ra} ₁ ^l ₈ ^{kyl, -Ar4 and -Het4}

6^{, ;}

R ^{, R} ₁₉ ^{, R} ₂₀ ^{, R} ₂₁ ^{, R} ₂₂ ^{, R} ₂₃ ^{, R} ₂₄ ^{, R} ₃₁ ^{, R} ₃₂ ^{, R} ₃₃ ^{, R} _{34 35 and R36 are each independently selected from–H, -halo, =O, -OH, -C1-6alkyl, -O-C1-} ^{15 6 oa}

–^pl

O^tk

H^ioyl

,^n,

-^{a - OllSy- -C aC}

1ⁿ¹

-^6d-6a

a^{lk inlk}

y^dy

l^,el,

-^{pSe -C}

-^{nCd3- 1e6c}

-^6ny

a^tlklcylo

y^{l sa}

,^{ul l,}

-^{Cbkys3t-6itcu - ytA}

c^er

l^d6

o^{a w a}

l^kintyhd

l^{, f -r–}

H^oHmet

e^t616;

, ^{- tAo w}

r^{63he sruebinstit euaecnhts o sfele sactided - fCro1-m6al–khyallo is,} R _{R37 a anndd R R8}

3_{8,, a arree e eaacchh in inddeeppeennddeenntlytly se sleelcetcetded fro frmom–H–,H -,C -1h-6aallok} ^a

,_y ⁿ _,C ^N

-_l ^d

O _- ^–

H_3,- ^R37

6 _-cCy ^R

1_c-6l ³

a_o ⁸

2_{7 2 la} ^;

k_{lykly,l - aOn-dC -1H-6et2: 20 C1-6alkyl, -C3-6cycloalkyl, -Ar7 an alkyl, -S- X s} ^6a _s ^lk _e ^y _l ^l _e ^-, _ct -_e ^N _d ^R _f ³ _r-_o ^, _m ^an _– ^d _C1 ^-O _-6a ^-; _lky ^w _l- ^h _, ^e _– ^r _{Od-C–1H-6aeltk7}

1 _{i ;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} s^{ubstituted with from 1 to 3 suebisntit each of said -C1-6alkyl- is optionally and independently} S_{-C1-6alkyl, -phenyl, and -NR33R3} ^{uents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, - 25} _{X 4}

2 _{is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} 6 ^{saulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C fr1o-6malk–yhl-al ios, o -OptHio,n -aCll1y-6a alknydl, i -nOd-eCp1e-6nadlkently S-C1-6}

c^{om4,p Aa}

r^ris5l,ky

i^{n Al}

g^{r,6 - 1,p ah}

t^{one yl, - Ar dny}

3 ^Al

h^{er a7n}

t^{e ad}

r^{roe -N}

a ^eR

t^oamc31

1^{, Ar hR}

s ⁱ³

sⁿ²

e^d;

l^{eepcetendde frnotmly O a, 5 N- t aon 1d0 S-m;e emacbhered aromatic cycle optionally 30 A} _fro ^r _m– ⁱ _h ⁿ _a ^g _lo ^o _, ^p _-O ^tio _H ⁿ _, ^a -^ll _C ^y _1- ^a _6a ^nd _lky ⁱⁿ _l, ^d -^e _O ^p-^e _C ⁿ ₁ ^d _-6 ^e _a ⁿ _lk ^t _y ^ly _l, ^s _-S ^ub _-C ^st ₁ ⁱ-^t ₆ ^u _a ^t _l ^e _k ^d _yl, ^w _a ^it _n ^h _d ^fr _– ^o _N ^m _R1 ^{1 of}

9_R ^{t soa 3id s Aurb1,s Atitru4,e Antrs5, s Aerl6 7 be e,c atnedd} C _{y and independently substituted with from 1 to230}

1_{-6alkyl is optionall ; - wherein each of said - Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-mhaelmo;bered heterocycl 35 having from 1 to 3 heteroatoms selected from O, N e}

H _{suebt and S; wherein each of said Het1, Het2 4s,tit Hueetn5 is , t,s H seetl6e,ct aendd fr Homet7–hal oop,t -ioOnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -(mC= 1O) t-oC13-} 6 _s ^a _u ^l _b ^k _s ^y _t ^l, _itu ^a _te ⁿ _d ^d _w -_i ^N _th ^R _f ² _r ¹ _o ^R _m ²² ₁ ^; _t ^w _o ^h ₃ ^er -^e _h ⁱ _a ⁿ _lo; ^{each of said -C1-6alkyl is optionally and indp d tly -29- Het8 O is a bivalent 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from we Nr}

5 _w ^h,

h_er ^{e a}

eⁱⁿ

i^nd

n ^{a S}

w^t _h ^l;

e^e _n ^as _R ^t ₁ ^o _i ⁿ _s ^e _– ^o _H ^f _, ^s _t ^a _h ⁱ _e ^d _n ^h _a ^{eteroatoms is attached to X1 or X2;}

w _{sehleerceteind s faroidm H–e t least one heteroatom of Het8 is attached to X2; and}

h_{t8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om -}

_{(C 1=O to)- 3C s1-u6ablsktyitlu,e -nCt1s-} 6 ^{inadlkeypl-eOn-C1-6alkyl and -NR21R22; wherein each of said -C1-6alkyl i pti lly and} ₁₀ ^{Z1, Z2, Z3, Z4d aenndtly Z s5u abrseti etuted with from 1 to 3 -halo;}

A _{M1o aroend}

m _{in A}

e_{r p2}

,_{a a}

r_rr

a_te

c_{iceu e}

m_laac

i_rh

c_{, th in}

m_ed

e _pe

t_arp ^{ach independently selected from C and N; and}

e_e

b_sn

o_ed

l_itne

e_tn

, _{itly selected from C and N.}

t_{aut n prvoe-n otiro pnre pdroruvigd,e ssa alt, c hoymdrpaoteun,d N- oofx Fidoerm fourmla, I oar o sro alva stteer tehoeirseoomf,er,}

^{15 Wh}

^I

R^{1 iesre}

(^{C si} h^=en e^Sle

r_e ^)c- _in ^Rte4d

e^, _a ^{- fr}

c^So

h^Om

o² _f ^-–RH

s⁴ _a ^{,, l,}

i_d ^-–Ch

-_C ^Na

1^, _-6 -_a ^{N -O}

l_k ^RH

y⁹ _l ^{-,S -OC1-6}

2^{-R4l,ky -Cl,3 --O6c-yCc1lo-6allkkyyll,, - -SO--CC1-6}

3^{-6clykcyllo,a -NlkRyl,9R -1A0r,1 -( aCn=dO)–-HRe4,t1 -} w ^; s_{ubst is optionally and independently substituted with from 1 to 3 R5 is attaictuheendts to se Zl1ec otred Z5 fro amnd– ihsa sloe,le -OctRed35, fr -oNmR1–1RH1,2,– -hO-C1-6alkyl, and -S-C1-6alkyl;}

20 _{alo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- 6}

6a^cylk^cy^lol,^a -^lkN^yR^l, ₆R ^-A ₇ ^r,⁵ - ^a(C^nd=O^–)^H-R^et ₈

5,^; - ^w(C^h=^erS^e)ⁱ-ⁿR ^e ₈,^ac -S^hO ^o ₂ ^f-R ^sa ₈,^id -C ^-CN¹,^-6 -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- s^{ubds -tSituted with from 1 to 3 substituents selected froma–lhkyallo is, - oOpRtio36n,a -lNlyR a23nRd24 in,d -Oep-Cen1-d6aelnktly an}

2_{5 i hsal oop,t–io} ^t-eC O_n ^d1-6 R_al ^f

2_l ^{ra yl, R2 is selec}

7_y ^olkmyl

n -_d ^h

, _{a an} ^–;

d^H _i ^, _e ^a _p ^lo _e ^, _n -_d ^O _e ^H _nt ^, _ly ^-C _s ¹ _u ^-6 _b ^a _s ^lk _ti ^y _tu ^l, _te ^a _d ^nd _w -_i ^C _th ^3-6 _fr ^c _o ^y _m ^clo ₁ ^alk _to ^yl; ₃ ^w _s ^h _u ^e _b ^r _s ^e _t ⁱⁿ _itu ^e _e ^a _n ^c _ts ^{h o} _s ^f _e ^s _le ^a _c ^id _te -_d ^C _f ¹ _r-_o ^6a _m ^lky _– ^l R_{3 is is se olpetciotendal flryomn R 4}

a_n–d

d_{H -N}

i_{,n -dh1}

e_a3

p_lR

e_o,1

n _-;

d_{OeHnt,ly -C s1u-6baslktiytul,}

l_{o,–OR28, and -NR15R16; te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanctsh o sfe sleacidte -dC f1r-o6amlky–l ha} ^-30- R_{4 and R8 are each independently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R ^{R 6alkyl, -NR17R18, -C3-6cycloalkyl, -O-C3-6}

7^{, R} ₉ ^{, R} ₁₀ ^{, cycloalkyl, -Ar4 and -Het4}

6^{, ; 5} _{R35 and R36} ^R _{1 a1r} ^, _e ^R _e12a ^, _c ^R _{h13 in} ^, _d ^R _e14p ^, _e ^R _n1d5e ^, _n ^R _tl1y6 ^, _s ^R _e1l7e ^, _c ^R _te1d8 ^, _f ^R _ro19m ^{, R} _–2H0 ^, _, ^R _-h21a ^, _l ^R _{o,22 =} ^, _O ^R _{,23 -} ^, _O ^R _H24, ^, - ^R _C31

1-^, _6a ^R _lk32y ^, _l, ^R _-3O3 ^R _-C34

1^,- 6 ^{oapltkioyln,a -llSy- aCn1d-6a inlkyl, -C3-6cycloalkyl, -Ar6 and–Het6; wherein each of said -C1-6alkyl is –OH, -O-C1-6alkydlependently substituted with from 1 to 3 substituents selected from–halo,} R _{and R8, are each} ^, _in ^-S _d-_e ^C _p ¹ _e ^-6 _n ^a _d ^lk _e ^y _n ^l _t ^{, -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38}

2_{7 2} ^;

R _{and R8, are each independenlyt selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2}

3_{7 3 : 10 X1 isC1 s-6ealelkcytle,d -C f3r-o6cmyc–loCa1lk-6yal ly selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S- l,k -yAl-r,7– aOnd-C–1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,ut -eNdR w3-i,th a fnrdom -O 1-; to w 3h seurebisntit euaecnhts o sfel seacitded -C fr1o-6malk–yhl-a ilos, o -OptHio,nally and independently} _{15 S-C1-6alkyl, -p} ^{-C1-6alkyl, -O-C1-6alkyl, -} X _{is selected frohmen–yCl,1 a-6nadlk -yNl-R,3–3RO3-4}

2 _{C;1-6alkyl-,–S-C1-6alkyl-, -C1-6}

6^a _{alkyl-NR3-C1-6alkyl-, -NR2-C1-} s^{ulbksytl-it,ut -eNdR w2-i, and -O-; wherein each of said -C1-6alkyl- is optionally and independently S-C th from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6}

1^{-6alkyl alkyl, - 20 Ar1, o A}

A^pr

r^{5t,i4o,n A}

A^arlr

6^l5

,^y,,

c ^{A -p aor}

n^{m6h,e dpr an Aisny r7idl an}

n^{g Ad be 1r7 -N in to aR y}

g ^{3re31R o hpe e3 tiota2}

e^{c; nrh}

a^{ola i}

l^ytnodme

a^nspe

d ^sned

i^{leecntetld f arom 5- O to, N 10 a-nmde Sm;b eearcehd o afr soamidat Aicr1 c,y Acrl4e, subst ndependently substituted with from 1 to 3} w_h ^{ituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19R20;} _{25 haerein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 - Het1 h,a Hlo}

v_e;

i_{nt2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro independently a 3- to 10-membered heterocycle Het4 m O, N and S; wherein each of said Het1, Het2,} 6 _{subs,tit Hueetn5t,s H seetl6e,ct aendd fr Homet7– ihsal oop,t -ioOnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -}

_{(mC= 1O) t-oC13-} ^{30 Het8 saulbksytl,itu atendd w -iNthR f2r1R22; wherein each of said -C1-6alkyl is optionally and indp d tly} a ⁱ _n ^s _d ^{a 3- to 10-meommbe 1re tod 3 he -htearloo;cycle having from 1 to 3 heteroatoms selected from O, N} w _{sehleer S}

c_e;

t_{eind s faroidm H–eht8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om - 1 to 3 su}

3⁵

_{(C=O)-C1-6ablsktyitlu,e -nCt1s} d- i ⁶

w^{nalkyl-O-C1-6alkyl and -NR21R22; wherein each of said -C1-6alkyl i pti lly an} h^d _e ^e _r ^p _e ^e _in ^nd _w ^e _h ⁿ _e ^tl _n ^y _R ^su ₁ ^b

a_{r is} ^st

e_– ^it

e_H ^ut

a_c, ^e

h _t ^d _{h ie} ^w

n_n ^ith

d_{e apt} ^fr

e _le ^o

n_a ^m

d_set ¹

n _o ^t

t_ln ^o

y_e ³

s _h - e_e ^h

l_et ^a _e ^lo;

Z _{ctreodat foromm o Cf H aentd8 i Ns. attached to X2}

1_{, Z2, Z3, Z4 and Z5} ^{-31- M taourtoem iner p,a rraticceumlairc, th mee ptarebsoelintet, in pvreon-t oiorn p prerodvruidge,s s aalt c,o hmypdorautned, N of-o Fxoidrmeu folarm Ia, o orr a so sltereoisomer, wherein vate thereof,} 5 ^{R1 is} _{( wC} ^s

h₌ ^e

e_S ^le

r_e) ^c _-inR ^{ted from}

e_{ach of-} ^– _R ^{H,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6}

4_{, -SO2 s4a,id -C -CN1,-6 -aNlkRy9l- iSsO o2p-tRio4n,a -lCly3- a6cnydcl ionadlekpyel,n -O-C3-6} ^a _c ^l _y ^k _c ^y _l ^l _o ^, _a ^-N _lk ^R _yl, ^9R -¹ _A ⁰ _r ^, ₁ ^-( _a ^C _n ⁼ _d ^O) _–-_H ^R _e ^4, _t1 -_{; substituents selected from–halo, -OR35, -NR11R12, -O-Cdently substituted with from 1 to 3 R Z 1-6}

5 _{is attached to 1 or Z5 and is selected from–H,–halo, -OalHky,l -,C a1n-6da -lkSy-lC,1 --O6a-lCky1-l6;alkyl, -S-C1-} ¹⁰ ₆alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- 6 ^{scuybcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteitiune enatsch se olefc staeidd f -C1-6alkyl is optionally and independently} a_n ^{rom–halo, -OR36, -NR23R24, -O-C1-6alkyl,} R_{2 is sdel -eSc-tCe1d-6a frlokmyl;–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl,; wherein each of said -C1-} ^{15 6alkyl is optionally and i}

R ^{is–h ; stituted with from 1 to 3 substituents selected from 3} _op ^sa

t^el

i_o ^loe,

n^c–

a^t _l ^eO

l_y ^dR

a ^f2

n^ro7,

d^{m an}

i_n ^–d

d^{H -} e_p ^,N

e ^-Rh _n ^{a1n3dependently sub} d^l _e ^oR

n^,14

t -_ly ^O _s ^H _u ^, _b -_s ^C _ti ¹ _t-_u ^6a _te ^lk _d ^y _w ^l, _i -_t ^C _h ³ _f-_r ⁶ _o ^c _m ^yc ₁ ^loa _to ^lk ₃ ^yl _s ^; _u ^w _b ^h _s ^e _ti ^r _t ^e _u ⁱ _e ⁿ _n ^e _ts ^a _s ^ch _el ^{of said -C1-6alkyl is} O_{R2 ected from–halo,–} ²⁰ _{R 8}

4 _{and R,8 an adre -N eRa1c5hR1 in6;dependently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R ⁶

6^{, Ra} ₇ ^{l,ky Rl,} ₉ ^{, -N RR17}

1₀ ^{,R R18}

1₁ ^{,, - RC3-6}

1₂ ^{,c Ry} ₁ ^c ₃ ^{l,oa Rlk} ₁₄ ^{y,l, R -} ₁ ^O ₅ ^{,-C R3-6}

1₆ ^{c,y Rc} ₁ ^lo ₇ ^{,a Rlk} ₁ ^y ₈ ^{l,, - RA} ₁ ^r4

9^{, a Rn} ₂ ^d ₀ ^{, - RH} ₂ ^e ₁ ^t4;

R _{R re each independently selected from–H, -hal} ^, _o, ^R _=2O2 ^, _, ^R _-O23H ^{, R} _{, -2C4} ^, _1- ^R ₃₁

6_alk ^, _y ^R _{l,3 -2 34, 35 and R36 a O} ^{, R} _-C33

1^,- 6^{alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Ar6 and–Het6; wher}

2^{5 optionally and independently substituted with from 1 to 3 suebins each of said -C1-6alkyl is} R_{27 a} ^– _n ^O _d ^H _R ^, ₂ -₈ ^O _,- _a ^C _re ^1-6 _e ^a _a ^lk _c ^y _h ^l, _in ^-S _d-_e ^C _p ¹ _e ^-6 _n ^a _d ^lk _e ^y _n ^l _t ^, _ly ^-C _s ³ _e ^-6 _le ^c _c ^y _t ^c _e ^lo _d ^a _f ^l _r ^k _o ^y _m ^{l, -} _– ^H _H ^e _, ^t6 _-C ^{, - tituents selected from–halo,}

1^A _-6 ^r _a ⁶ _lk ^a _y ⁿ _l ^d _{, -} ^– _C ^N _3- ^R37R38;

R _{dependently selected from–H, -halo, -OH,6}

3_{7 and R38, are each in -cCy1cloalkyl and -Het2: C -6}

1_{-6alkyl, -C3- alkyl, -O-C1-6alkyl, -S-} ³⁰ _{X o6}

1 _{is selected frcmyc–loCa1lk-6yall,k -yAl-r,7– aOnd-C–1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} X ^{6a - A2r1 i,s el o A slek prti4ly o,c-, n Ate a alrl5dnd y, fr}

c ^{Ao -N ormR m6,–3 pr aO; isn- idC2}

n^{g A-3}

1^ra7lk

t^{o ayl}

3^r-e,–

h^{e eS}

t^{a- ecC}

r^h2-3

o^{a ia}

t^nl

o^dky

m^el

s^{p-,e - snN}

e^dR

l^{eecn2- tetCly2-3}

d ^{f aalk}

r^{om 5y-l-,}

O ^{to -N}

, ^{N 1R02}

a^{-- nm, a}

d^en

S^md

;^{b - eeO}

a^rce-;

h^{d o afr soamidat Aicr1 c,y Acrl4e,} _{35 A}

w _sur5

h_b,

e_{srt A}

e_{itiur6e,nt asnd sel Aerc7te bdei fnrgom op–thioanloa,lly -O aHn,d -C in1d-6eaplkeynld,e -nOtl-yC1 s-6uablksytilt,ut -eSd-C w1-i6tahlky frlo,m–N 1R1 t9oR203; halo; n each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 -} ^{-32- Het1 h,a Hveint2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro inmde Op,e Nnd aenndtly S a; w 3h-e tore 1in0- emaechmb oefr seadid h Heteetr1o,c Hyecle} H_{et4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to} ^t2 ₃ ^{, 5} _{substituents selected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

_(C=O)-C1- 6^{alkyl, and -NR21R22; wherein each of said -C1-6alkyl is optionally and indp d tly Het8 su}

a ⁱ _n ^{sb asti 3tu-te tod 1 w0it-hm ferommbe 1re tod 3 he -htearloo;cycle having from 1 to 3 heteroatoms selected from O, N} _{10 w sehd}

l_{eer S}

c_e;

t_{eind s faroidm H–eht8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om -}

_{(C 1=O to)- 3C s1-u6ablsktyitlu,e -nCt1s-} 6 ^{inadlkeypl-eO-C1-6alkyl and -NR21R22; wherein each of said -C1-6alkyl i pti lly and whe ndently substituted with from 1 to 3 -halo; 15 Z rein when R1r ise– eHac,h th iennde apte lenadsetn otlnye s heeletectreodat foromm o Cf H aentd8 i Ns. attached to X2}

1^{, Z2, Z3, Z4 and Z5 a}

I ^{snter aeo fuisrothmeerr, em tabuotodmimeer,nt r,ac theemic p,re mseentatb ionlviteen,t piorn provides a compound of Formula Ia or a} s_{olvate thereof, whe} ^{o- or predrug, salt, hydrate, N-oxide form, or} R_{1 is selected fromrein}

2_{0 ( wCh=eSre)-inR4 e,a -cShO o2f-–RH}

s_4a,,

i_{d -–Ch}

-_CNal

1_,o,

-_{6 -aN -O}

l_kRH

y_9l-,

i_{S - sOC1-6}

o_2p-tRa

i_o4l

n_,ky

a _-lCl,

l_{y3 --O}

a_{6c- nyC}

d_{c1l io-6}

n_aa

d_ll

e_kk

p_yy

e_{ll,, - n -S}

d_{O- e-C}

n_C1-6

t_l3y-6a

s_cl

u_ykcy

b_ll

s_o,N

t_{a - itlukR}

t_{yeld,9R -1}

w_A0

i_r,

t_{h1 -(}

f _{aC rn= odO)- m– 1HR te4, ot1 - 3; R is su abtstatictuheendts to se Zl1ec otred Z5 fro amnd– ihsa sloe,le -OctRed35, fr -oNmR1–1RH1,2,– -hOa-loC,1- -6OalHky,l -,C a1n-6da -lkSy-lC,1 --O6}

5 _{a-lCky1-l6;alkyl, -S-C1-} ²⁵ ₆alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- 6 ^{scuybcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteitiune enatsch se olefc staeidd f -rCom1-6a–lhkyallo is, - oOpRtio36n,a -lNlyR a23nRd2 independently and}

i^{s ope - 4, -O-C1-6alkyl, R2 is selS}

t^ciot-eC6

n^{d1- al flra}

y^olkmyl

a^n–;

d^{H i,n -dheapleo,n -dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanctsh o sfe sleacidte -dC f1r-o6alkyl} _{30 R halo,–OR27, and -NR13} ^m– 3 _{is selecte R14;}

i_{s d from–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl ha optionally and independently substituted with from 1 to 3 substituents selected from– 35 i R, Rlo,–OR28, and - RN1R15}

2_{, RR16}

6 _{7, R9, R10, R11, 13,; R14, R15, R16, R19, R20, R21, R22, R31}

6_n ^c _d ^y _e

b^cl _p ^o _e ^a _n ^lk _d ^y _e ^l, _nt -_ly ^Ar6 _se ^a _le ⁿ _c ^d _te ^– _d ^He _fr ^t _o ^6; _m ^wh _– ^e _H ^r _, ^ei -ⁿ _ha ^e _lo ^a _, ^ch _=O ^of _, ^s -^a _O ^id _H, ^-C _-C1-6

1^-6a _{alkyl, -O-,C R32}

1_{-6a,l Rky3l3, a -nSd-C R34}

1_{-6a alkryel, e -aCc3h- su-6sctyitculoteadlk wyli,th -H ferot6m, -A 1r t6o an 3d s–uNbsRti3t7uRe3n8t;s selected from–h} ^l _a ^k _l ^y _o ^l _, ⁱ _– ^s _O ^o _H ^p _, ^ti -^o _O ⁿ-^a _C ^ll ₁ ^y _-6a ^a _l ⁿ _ky ^d _l, ⁱⁿ _-S ^d-^e _C ^p ₁ ^e _-6 ⁿ _a ^d _lk ^e _y ⁿ _l ^t _, ^ly C_{3 -} ^{-33- R R27 and R28}

3^{8,, a arree e eaacchh in inddeeppeennddeenntlytly se sleelcetcetded fro frmom–H–,H -,C -1h-6aallok,y -l,O -CH3,-6 -cCy1c-6laolaklkyl and -Het2 37 and R :} C_{1-6alkyl, -C3-6c}

5 ^6a _my ^{yl, -O-C1-6alkyl, -S-} X_{1 is selected fro c–lo k}

d_{Ca1l-6yall,k -yAl-r,7– aOnd-C–1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} s^{ulbksytl-it,ut -eNdR w3-i,th a fnrom -O 1-; to w 3h seurebisntit euaecnhts o sfel seacitded -C fr1o-6malk–yhl-a ilos, o -OptHio,n -aCll1y-6a alnkydl, independently} S_{-C1-6alkyl, -phenyl, and} ^{-O-C1-6alkyl, -} X _-NR33R34

2 _is ^6a _{selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2-C1-} ^{10 sulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C fr1o-6malk–yhl-al ios, o -OptHio,n -aCll1y-6a alknydl, i -nOd-eCp1e-6nadlkeynlt,ly - Ar S-C}

o^pr1-6

t^i4o,a

n ^Al

a^lrk

l^5y

y^,l,

c ^{A -p}

o^rm6h,e

p^{r an}

i^sny

i^{dl an}

n^{g Ad}

1^{r7 -N}

t^{o aR}

3^re31

1^{, A R}

h^{e e3}

t^a2

e^c;

r^{hoa itnodmespe snedleecntetlyd f ar 5- to 10-membered aromatic cycle 15 Ar5, Ar6, and Ar7 being optionally and independoemntl Oy, N and S; each of said Ar1, Ar4, s} _w ^u _h ^b _e ^s _r ^t _e ^it _i ^u _n ^e _e ⁿ _a ^ts _ch ^se _o ^l _f ^e _s ^c _a ^te _id ^d - ^f _C ^{rom–halo, -OH, -C} _1-6 ^a _n ^l _d ^ky _in ^l, _d -_e ^O _p-_e ^C _n1d-6 ^{substituted with from 1 to 3}

1_{-6alkyl is optionally a e} ^a _n ^lk _tl ^y _y ^l, _s -_u ^S _b-_s ^C _ti1tu-6t ^a _e ^lk _d ^y _w ^l, _it ^a _h ⁿ _f ^d _ro ^– _m ^N ₁ ^R _{1 t9o} ^R ₂₀ ^; t_{1h,a 3 - He Hloe;t2, Het4, Het5, Het6, and He}

2_{0 having from 1 to 3 heteroatomt7 are each independently a 3- to 10-membered heterocycle}

H _{suebtstituetn5t,s H seetl6e,ct aendd fr Homet7– ihss}

a_{l o s}

o_{pelected from O, N and S; wherein each of said Het1, Het2 4, He ,}

,_{t -ioOnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -}

_{(mC= 1O) t-oC13-} 6 ^{saulbksytl,itu atendd w -iNthR f2r1oRm22; wherein each of said -C1-6alkyl is optionally and indp d tly 25 Het8 a ins a 3- to 10-membe 1re tod 3 he -htearloo;cycle having from 1 to 3 heteroatoms selected from O, N} w _wh ^d

h_er ^S

e_re ^;

e_{in at least one of said heteroatoms is attached to X1 or X2;}

w_ehleercei

t_{einn w}

d _{s fah}

r_oiedn

m _{H R}

–_{e1 is–H, then at least one heteroatom of Het8 is attached to X2; and s ht8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om -}

_{(C 1=O to)- 3C s1-u6ablsktyitlu,e -nCt1s} ³⁰ - 6 ^{inadlkeyl-O-C1-6alkyl and -NR21R22; wherein each of said -C1-6alkyl i pti lly and Z1, Z2, Z3p,e Zn4d aenndtly Z s5u abrseti etuatcehd i wnditehp feronmde 1nt tloy 3 se -lheacltoe;d from C and N.} _{35 In a st f}

s_oeu

l_vrreth

a_oe

t_{eisro thm em}

e_ererb,o

o _tfad

,_uim

w_toe

h_mnt

e_re,

e_{ri, th}

n _rae

e_{cae p}

c_mre

h_icse

o_{,f mnt}

s_{aeit in}

d_avbe

Z_on

1_l,itteio

Z_,n

2_{, pr p}

Z_or

3_-o

, _{ov finitions and provisions as defined herein above Zrid a4 pe pp arse}

l_{ynd a .dru Zg c}

5_,o

i _sm

s_{apl Cto,u}

; _hn

a_yd

n_{ddra o}

w_{tfeh, F}

e _No

r_-r

e_om

i_nxuidla

t_{hee f Ioa r frum o rt, o a her de r} ^{-34- In a st feurrethoeisrom emerb,o taduimtoemnte,r, th raece pmreicse, mntet inavbeonlitteio,n pr por-o ovrides a compound of Formula Ia or a solvate thereof, wherein said predrug, salt, hydrate, N-oxide form, or from 1 to 3 hetero Het8 is a saturated 3- to 10-membered heterocycle having} 5 _{provisions as defin} ^a _e ^t _d ^om _he ^s _re ^se _in ^le _a ^c _b ^te _o ^d _ve ^fr _a ^o _p ^m _pl ^O _y. ^{, N and S; and wherein the further definitions and} I _{snter aeo fuisrothmeerr, em tabuotodmimeer,nt r,ac theemic p,re mseentatb ionlviteen,t piorno- p orrov pidreedsru ag, c soamltp,o huynddrat oef, F No-ormxiudlea f Ioarm or a solvate thereof , or}

^{10 Wh}

^I

R^{1 ierein}

R ^{s–httalo 15 R2 i i l h;}

t^{dd f troom Z1– and is selected from–H and -C1-6alkyl;}

R^{3 is selected from H and -C1-6}

1^alkyl;

X _X ¹

2 ^{is sel} _t ^e _e ^d _d ^f _f ^r _r ^o _o ^{m Cn lC k} t _{is sel} ^e _e ^c _c ^t _m ^––

–^OH

O^{- a}

-_C ^1d-6

1_-6 ^{a -} a_lk ^ky- y^l6

l^-a

-^,l

, _- ^-Ny

N^Rl;

R³

2--^C _C ^1-6

1_-6 ^a _a ^l _l ^k _k ^y _y ^l _l--^, _, - -^N _N ^R _R ^{3-, -O-;}

H_{e substitute-d t}

, _{woith 101-m toe 3m sbuebresdtitu Nen-ctosn stealiencintegd h freotmer2}

8 _{is a 3 o- –c,}

h_{y -O}

a_clol-e;

,_{; -O wHh,e–reCin1-6a slakiydl, - HOe-tC8}

1_{- i6salk oypl,tio -Sn-aCll1y} ²⁰ - _Z ⁶

1_{, Z2} ^a _, ^lk _Z ^y ₃ ^l _, ^, _Z ⁼ ₄ ^O _an -_d ^(C _Z ^=O)-C1-6al _h ^ky _C ^{l, -C1-6alkyl-O-C1-6alkyl and -NR21R22}

^{; and}

^-35- _{More in particular the present invention provides a compound selected from the list comprising: C}

_{p d N1 E pl N1 Cp d N2 E pl N2}

C

_{p d N3 E pl N3 Cp d N4 E pl N4}

C_{p d N5 E pl N5 Cp d N6 E pl N6}

C

_{p d N7 E pl N7 Cp d N8 E pl N8} ^-36-

_C

_{p d N9 E pl N9 Cp d N10 E pl N10}

_{Cp d N11 E pl N11 Cp d N12 E pl N12}

_C

_{p d N13 E pl N13 Cp d N14 E pl N14}

^C

^{p d N15 E pl N15}

I _in ⁿ _v ^a

e_{e nn} ^fu

u_ti ^r

m_o ^th _n ^er

b_{,e w} ^p

r_inh ^a

g_e ^r _r ^t

a_e ^ic

s_in ^ula

p _R ^r

r_o5 ^e

v _iis ^m

d_{e l} ^b _idn ^o _k ^d

i_ne ^im _d ^e

F_{o to} ^nt

r_{m t} ^, _h ^t

u_e ^he

l_{a a Ir} ^p _y ^r

o_l ^e

r _o ^s

I_ar ^en

. _h ^t _e ⁱ _t ⁿ _e ^v _ro ^e _a ⁿ _r ^t _y ^io _l ⁿ _m ^p _o ^r _i ^o _e ^v _ty ^id _a ^e _t ^s _p ^a _o ^c _s ^o _iti ^m _on ^po _Z ^u ₁ ⁿ _i ^d _n ^a _a ^c _c ^c _c ^o _o ^r _r ^d _d ⁱ _a ⁿ _n ^g _c ^t _e ^o _w ^th _it ⁱ _h ^s _th ^{-37- I tnhis ye intv ae fnutriothne,r w phaerrteiciunla srai edmbodiment, the present invention provides a compound according to In yet a further particular em cboomdpiound is the S-enantiomer.}

t^{hi ment, the present invention provides a compound according to 5 I cts}

o^{m is inv}

p^{r aen}

i^{sin futi}

g^rotnh,

a^{e wrh}

c^{o oe}

m^brje

p^ei

o^{cnt sa}

u^{n oi}

d^fd

a ^{t cho}

c^emp

c^{o po}

r^dreu

i^nsn

g^{edn i}

t^{ts t}

o ^ihne

t^{vhe R}

i^{sn-tei ion}

n^nan

v^{en ttoiom}

t ^{preorv.ide (pharmaceutical) compositions compositions according to t ion. In particular, the compounds and The compounds and comphoissi itniovnesnti aocnco arrdein sguit taobl tehi fsor in uvseen atison a h auman or veterinary medicine. 10 activity of a kinase, in particula re suitable for inhibiting the p Inre ave finntaioln r LRRK2 kinase, and may be used for the treatment and/or ob ojefc nteivuero,l tohgeic parle dsiesnotrd inevresn stuiocnh p arso Alzheimer’s disease or Parkinson’s disease.}

o^{f a neurological disorder, such as Alzheimveidr’ses d aise maesteho odr f Porar thkiens porenv’sen dtiisoena asend/or treatment comprising administering to a subject in need there ; said method} t_{o this i} ^{of a compound or a composition according} _{15 nvention.}

D _{T IN}

o_fhEeTA

t_{he prIeL}

i_nsE

v_eD

e_{nnt D}

t_{i ionE}

n_vSeC

a_nrtR

e_ioIP

d_nT

e _wIO

f_iinllN

e _{ndo O}

i_wF

n _{b T}

m_eH

o _fE

r_{uert dheeV}

t_rE

a _dN

i_l.eT

E_scIO

a_rcibN

h_{e ads.p Inec thte so fo dlleowing passages, different aspects 20 other aspect or aspects unless clea fined may be combined with any i fnedaitcuaretesd in adsica bteeidng as p breefienrgre pdre oferrr aeddv oar}

r_nly

a_{tadg in}

v_ed

a_oic

n_ua

t_{aste mda tyo b thee co cmonbtirnaeryd. w Inith pa arntiycu olathr,er an feyat fueraetu orer U mnolneos-s o ar c boivnatleexntt d riacdtaictaels d oetphiecrtwedise is, c aosntenreiscktesd ag}

t_re

o_eo

t _uu

h_ss

e_e.

s_{dtr huecrteuirne t too i wndhiiccahte it r theelat peosin atn adt o wfh wichhic a 25 the radi}

o_{f Formacdayl f mo h As alre remnstio pnaertd. hereinbefore, in a first aspect the present invention provides compounds oxide fourmla, I o orr s aolv satetere tohiesroemoefr, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-}

_Wherein

^{I -38- R1 is}

w^{(C s=eSle)c-Rte4d, - frSoOm2-–RH4,, -–ChNal,o, -N -ORH9-,S -OC1-6}

2^{-Ra4l,ky -Cl,3 --O6c-yCc1lo-6aallkkyyll,, - -SO--CC1-6}

3^{-6aclykcyllo,a -NlkRyl,9R -1A0r,1 -( aCn=dO)–-HRe4,t1 -;} 5 _{suhbesrteiin each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 R5 is 6}a _alk_tty_al,_ctuhe

-N_endts

R_{6 t}R_{o se}

7 _Zl

,_1ec

-( _{oted from–halo, -OR35, -NR11R12, -O-C1-6alkyl, and -S-C1-6alkyl;}

C_r= _ZO₅)- _aR_n8d, _i -_s(C _s=_eS_le)_c-R_te8d, _f -_rS_oO_m2-_–R_H8,_, -_–C_hN_al,_o -_,N _-OR_6H-S_,O _-C1-6

2-R_a8,_lky -C_{l,3 --6O}c-y_Ccl₁o_-6a_al_lk_ky_yl_l,_, - -O_S--_CC_{1- 3-} 6 ^{scuybcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteiin each of said -C1-6alkyl is optionally and independently 10 and -S-C1-6a tuents selected from–halo, -OR36, -NR23R24, -O-C1-6alkyl, R2 is is se olpetciotendal flryolkmyl}

a^{–;H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl} h_{alo,–OR27, an} ⁿ _d ^d - ⁱ _N ^nd _R ^e ₁ ^p _3R ^en ₁₄ ^{dently substituted with from 1 to 3 substituents selected from–} R_{3 is}

1_{5 is se olpetciotendal flryom an–dH i,n -dheapleo,n -;}

d_{OeHnt,ly -C s1u-6baslktiytul,te adnd -C3-6cycloalkyl; wherein each of said -C1-6alkyl R ahnadlo, R– with from 1 to 3 substituents selected from–}

8_{O aRre28, e aancdh - iNnRde15pRe1n6}

4 _{d;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R^{, R 6a7l,ky Rl,9 -NR17R18, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar4 and -Het4}

6 ^{; 20} _R ^{, R10, R11}

6^, _a ^R _re ^12, _ea ^R _c ¹ _h ^3, _in ^R _d ¹⁴ _e ^, _p ^R _en ¹⁵ _d ^, _e ^R _n ¹ _t ⁶ _ly ^{, R} _se ¹ _l ⁷ _e ^, _c ^R _te ¹ _d ^8, _f ^R _ro ¹ _m ^{9, R} _–H ²⁰ _, ^, - ^R _ha ²¹ _l ^, _o, ^R ₌ ² _O ^2, _, ^R _-O ²³ _H ^{, R} _{, -} ² _C ^4, _1- ^R31

3_{4, R35 and R3 6alk} ^, _y ^R _l, ³ -² _O ^{, R} _-C ³³

1^,- 6 ^{oapltkioyln,a -llSy- aCn1d-6a inlkdyel,pe -Cnd3-e6cnycloalkyl, -Ar6 and–Het6; wherein each of said -C1-6alkyl is} –_{OH, -O-C1-6alkyl, -S-C1-6a} ^t _lk ^ly _yl ^{substituted with from 1 to 3 substituents selected from–halo,} R _{and R28 are each independentl,y -C se3l-e6ccytecldoa frlokmyl,– -HHe,t -6, -Ar6 and–NR37R38}

2_{7 ;}

R_{7 and R38 are each independently selected from–H, -Ch1a-6loa,lk -yl, -C3-6cycloalkyl and -Het2}

3 _: ²⁵ _{OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- X} ^{6alkyl, -C3-6}

1 _{is selected} ^c _f ^y _ro ^c _m ^loa _– ^lk _C ^y ₁ ^l, _-6 -_a ^A _lk ^r7 _yl ^a _-, ^nd _–O ^–-^H _C ^e ₁ ^t7

-₆ ^; _{alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,ut -eNdR w3-i,th and -O-; wherein each of said -C1-6alkyl- is optionally and independently} S_{-C1-6alkyl, -phe} ^f _n ^r _y ^{om 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -} _{30 X2 is} ^6a _s ^lk _e ^y _l ^l _e ^-, _ct -_e ^N _d ^R _f ² _r-_o ^, _m ^an _– ^d _{Cl,1 a}

-^O _-6nad

-^; _{lk -yN}

w_l-R

h_,3

e_–3R3

r^e _O ⁱⁿ _-4C;

e_1- ^a _6a ^ch _lky ^o _l- ^f _, ^s _– ^a _S ^id _-C -₁ ^C _-6

1_a ^-6 _lk ^a _y ^lk _l- ^y _, ^l- _-C ^is _1-6 ^o _a ^p _lk ^ti _y ^o _l- ⁿ _N ^a _R ^lly _2-C ^an _{1-6alkyl-, -NR2-C1-} s^{ubstituted with from 1 to 3 substituents selected from–halo, -OH, -C1-6alkydl, i -nOdependently S-C1-6alkyl, -phenyl and -NR31R32 -C1-6alkyl, -} ₃₅ ^Ar1, _o ^{Ar4, Ar5, Ar6, and Ar7 are eac;h independently}

A_{pr5t,ion Aarl6l,y c aonmdpr Aisr7ing be 1in tog 3 o hpetiotenraolalytom ansd se ilnedcetepden f} ^a _rdoem ^5- n_{tl O} ^to

y_{, s N} ¹⁰

u_{b a}- s_n ^m

t_d ^e

i_{tu S} ^m

t_e; ^{bered aromatic cycle} d _{ea wchith of f sroamid A 1r1, Ar4, substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR1 t9oR203 wherein each of said -C1-6alkyl is optionally an ; halo; d independently substituted with from 1 to 3 -} ^{-39- Het1 h,a Hveint2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro inmde Opendently a 3- to 10-membered heterocycle} H_{et4, He} ^{, N and S; wherein each of said Het1, Het2, 5} _{substituetn5t,s H seetl6e,ct aendd fr Homet7– ihsal oop,t -ioOnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -}

_{(mC= 1} 6^a _{O) t-oC13-} s^{ulbksytl,itu atendd w -iNthR f2r1oRm221; t woh 3er -ein each of said -C1-6alkyl is optionally and indp d tly Het8 a insd a 3- to 10-membered hehtearloo;cycle having from 1 to 3 heteroatoms selected from O, N 10 w s e S -Oehl-ere; Cc1t-ein}

6^{ad s}

l^{k faryoid}

l^{,m H}

-^S–e

-^ht

C^{a8 is}

1^{l-o6a, o}

l ^-kOpt

y^lHio,n

, ^{=O–aClly ln p e s}

,^{1 --}

^{(6 a}

C^an

=^lkd

O^{y i}

)^,d

-^{C -Ce1-e6}

1^-6aan

l^kldkyyl,lnet

-^nly

C^{e1-, su}

6^{a -Cb}

l^k1y-t6i

l^-atu

O^lkte

-^yd

C^{l-1C w3i-t6h}

-^{6alkcyy f}

l^cro

a^lom

n^{adlk 1}

-^{y t}

N^{l,o - 3C3 s-6ucbysctliotuaelknytsl, each of said -C1-6alkyl is optio lly d idp dently substituted with from 1R t2o1R 322 -;ha wlherein wherein when R1–H, then at l t ht tom of Het8 is atached to X2 o; 15 Z1 t}

A^{1, a Zn2d, Z A3}

2^{, a Zr4e a enadc Zh5 in adreep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and U X1nl iess -sN inRd3i-cCated otherwise, all of the above radicals can be read both ways. For example, when aryl or heter1o-6aalkyl-, the -C1-6alkyl- may be attached to Het8 and–NR3- attached to the Z1-Z5 20 h eexreate}

f^mro

e^rpa

a^lery

b^{l wl}

y^{,h m}

X^{eonieryl moiety. Alternatively, the -C1-6alkyl- may be attached to the Z1-Z5 aryl or Xty1 is an -NdR–3N-CR3}

1^{-6-al aktytal-c,h -NedR3 t-o, a Hnedt8 th.e W“rhigahtt is pa crta”ll iesd -C“1le-6ft part” of a radical is for P 1 is such as the left par alkyl-.}

C_{1-6alkyl, -S from–S-C1-6alkyl, -N} ^{t of the possible values of X1 (i.e. in particular–O from–O-} _{25 heteroaryl moiety. Alternatively R3 from -NR3-C1-6alkyl, etc) is attached to the Z1-Z5 aryl or p Za1-rZti5cu alrayrl o (Cr1 h-6eatelkryola)- is}

r_{y from–O-C,1 X1}

-_{6alky sl,uc–hS- aCs1- t6haelky rilg ahntd pa -rNtR o3f- tCh1e-6a ploksysl,ib eletc) va islu aetsta ocfh Xed1 ( tio.e. th ine PCr1e-6faelrkaybl,ly, - XS2 is fr soumchl a m}

–_so

S_{- tChieety}

1_{-6 lae.}

l_{fkty pla,rt - oNfR th2e possible values of X2 (i.e. in particular–O from–O- 30 pyrzolopyrimidine moiety. Alternatively, X2 i fsro smuch -N asR t2h-Ce1 r-i6gahlkty pl,art e otcf) the is pos astitbalceh veadlue tso of th Xe ( .a 2 toi.e the in p pyarartzicoulolapryr (iCm1i-d6ainlkey ml)-o fireotym.–O-C1-6alkyl,–S-C1-6alkyl and -NR2-C1-6alkyl, etc) is attached T Whhee snam dees pcrriibnicnipgle th aepp clioemsp toou anlld thse o rfad thiceals in ovef tnhtieon in,ve thnetion unless specified otherwise.}

a_{ccordance with the following definitions, unless a context d teicrms used are to be construed in 35 T rahde}

o_{ic taelrsm. G "aelnkyelr"a bllyy, it asleklyfl o grr aosup psar otf o tfh aisno inthveernt siounbs ctiotumepnrtis reeftea}

f_rrt

o_ses

m _{to ot}

1 _fhue

t_lloyrw

6 _sisae

c_tu:

a_{rated hydrocarbon grbuspcsrip mt iasy us beed l hineeraerin o froll borwainncghe ad ca arnbdon m aatoym b,e the su sbusbtistucrteipdt r aesfer isnd toica thteedrb}

n_{u ho}

m_{enrbe a}

e_{into r.m o Ws. f ch Alkyl su aernbo an} ^{-40- a sitxom casrb thoant t ahteom nas.m Eexda gmropuleps m oafy al ckoynlt garionu.p Tshu asr,e fo mre ethxaylm,p elteh,y Cl,1 n-6-aplrkoyply ml,e ia-pnrsop aynl, a blkuytly ol,f a one to isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isom nd its alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbers. C1-C6 5 a t-nbdut tyhl)u;s p iennctlyuld aensd m ietsth isyol,m etehrysl,, h ne-pxryolp aynl,d i- iptsro ipsoylm, beursty,l c ayncdlop itsro ipsyolm, ceyrsc (e.g. n-butyl, io-bnu atytlo amnsd, cycloh lobutyl, cyclopentyl, and T mhoere tee}

s^rumxy

b^{s "l.otitputeionntasll (yfo sru ebxsatimtupteled 1 al tkoyl 3" r seufbesrstit tuoe an alkyl group optionally substituted with one or 10 s inucblusdtiteue–nhtasl)o, at -O aHny, p arvimailaarbyle an pdoin stec oofn adttaarcyhmenntst., N foorn e-xlimamitipnlge e 1x,a 2m oprle 3s s oufbs stuitcuhen stusb osrtit 1ue tont 2s and the like amides, -O-C1-6alkyl, -S-C1-6alkyl, heteroaryl, aryl, T sahye, te arm mo“c.}

n^{yocvloaalelknyt,l” by itself or as part of another substituent is a cyclic alkyl group, that is to} _{15 C hyydcrlooacalkryblon inc glurodue} ^{saturated, or unsaturated hydrocarbyl group having a cyclic structure.}

p_{ss a hll saturated or partially saturated (containing 1 or 2 double bonds) carbon atoms in the rinagv ainngd a cyclic structure. Cycloalkyl groups may comprise 3 or more Examples of cycloalkyl grou generally, according to this invention comprise from 3 to 6 atoms. 20 cyclohe ps include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, W othheerre g axylkl.yl groups as defined are divalent, i.e., with two single bonds for attachment to two includeroups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups ethyles methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, 25 Genertahlylyle,n aelk,y 1l,e2n-edim gethylethylene, pentamethylene and hexamethylene.}

a _{cotonmnesc ativsity th teoir th aelk mylr}

o _{coouupnste orpfa trhtiss. in Wvehnetiroen a pnre afelkryalbelnye c oorm cpyricsleoa tlhkeyle snaeme bir naudmicbaelr is of pr ceasrebnont, atom or different carbleocnular structure of which it forms part may be through a common carbon invention, a C3 alkylene atom. To illustrate this applying the asterisk nomenclature of this CH2CH(-CH3)-*. Likewise a gr Cou3p cy mcloa}

*_{aylk byelen foer g eroxaumpp mleay *- bCeH2CH2CH2-*, *-CH(-CH2CH3)-*, or *-}

³⁰ * *

T^{arhoem taetricm,s fu "llhye steartoucraycteled" o ars pa ursteiadl h}

^{i by it lf prt of another group refer to noend- monoc ly t td yli g ps (for example, 3 to 6 member} _{35 contain} ^y _in ^cl _g ^{ic ring systems) which have at least one heteroatom in at least one carbon atom-} 4 _{su hbestteitruoteadto rming. Each ring of the heterocyclic grouyp containing a heteroatom may have 1, 2, 3 or heste sreolceycctelicd r ferofemrs n tiotro age hnete artoomcysc,li ocx hagveinng at oopmtiosn aanlldy/o orn seu olfrur m aotroem ssu.b Asntitu oepntitosna (flolyr} ^{-41- e suxabmstiptulete 1d t aolk 4 substituents, or for example 1, 2, 3 or 4), selected from those defined above for E isxoexmazpolalry heytel.rocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, 5 i pnydroroly inyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- lil, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3- homopniyple,raz pinyyrrl,oli 2d-inpyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, dihydro- 2H-pyranyl,yra pzhotlhinaylal,zin 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4- 10 dioximidazolidinyl, 2,2,4-piperidoynly,l, ox 2e-toaxnoypl,i thietanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5- i tnedtroalhinyydl,roiso teqturainhoylidnryolp,y thraionmylo,rph toeltinrayhl,y tdhrioofmuroarnp}

p^ye

h^lo,ridin

l^{iny ty}

l^el

s^{t,ruelh 2}

f^oyxd-o

i^{rxopyrrolodinyl, 2-oxoazepinyl, doethienyl, tetrahydroquinolinyl, dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H,-1 t,h2io,5m-tohripholinyl sulfone, 1,3- dithiazinyl, 2H-oxocinyl, 1H-pyrrolizinyl, tetrahydro- 1,1-dioxothienyl, N- foardmiayzlpinyl, 2H-1,5,2- morpholinyl; in particular pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidiniyple,ra dzioinxyl, and 15 d piyorxroalnyl, morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyorlaannyyll,, azabicoypciploe[r2a.2zi.n1y]hl,eptanyl, 3-azab oicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 2- a]pyrazinyl, 3,4-dihydro-2H-bencztaoh[6y]d[1ro,4p]yorxraozloin[1y,l2,-a] 2p-yorxaaz-in5y-al,zabicy occlota[4h.y1d.r0o]h-1eHp-tapnyryrlo,lo[11,,24-- 20 o Tx}

s_i ^ha

n^ez

g_l ^te

e^epr _r ^man

i_ng ^“yal,

(^r _i. ^{y a}

e^ln"d

. _p ^a _h ^{s te}

e ^utr

n^{sahydrofuranyl.}

y^e _l) ^d _. ^h _A ^e _ry ^re _l ⁱ _i ⁿ _s ^r _a ^{efers to a polyunsaturated, aromatic hydrocarbyl group having a} t_{he carbocyclic systems enumelrsaote indte hnedreedin. to N include the partially hydrogenated derivatives of biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-,o 3n-,-l 4im-,it 5in-,g examples of aryl comprise phenyl, 1-, 2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1- 2-, 3-, 4-, 6- o,r 7- 5,- oarc 8e-naazpuhletynleyl, 1- or 2-naphthyl, 25 a 5c-ienndaapnhytl,en 5y-,l, 61--,, 27--,, 3 o-r, 84--t,e otrra 1h0y-dprhoennaapnhtthhryyl,l, 11- or 2-pentalenyl, 1, 2-, 3-, onry 4l-,flu 3o-,re 4n-y,l, o 4r- 5 o-r di ,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, Thbeen azroy[la,d ri]ncgycl coahnep otepntiyoln,a alnlyd 1 b-e, 2-, 3-, 4-, or 5-pyrenyl; in particular phenyl.}

s_{ubstituted aryl” refers to an aryl ha svuinbgst oitputtieodna bllyy o onnee or more substituents. An“optionally 30 s duebfisnteitdue anbtosv,e fo fror ex saumbsptilteut 1e,d 2 a,l 3 or 4) at any available p oori mnto oref a stutabcshtimtueenntt,s s (efolerc etexdam frpolme 1 th toose 5 W refheerrreed a to c haerbreoinn a asto am in an akryyll. group is replaced with a heteroatom, the resultant ring is 35 T}

o _tohe

x_{y 5 t}

g_{e teorm}

n_{, 6“}

n _ch

i_tae

r_orbte

g_or

e_no

n_-aar

o_{tyol” a hse rm su alfr ute uosr rmeo aada toti hry mcel s rr r}

i_{ein .nigng. Ns b}

o_{n iyn it}

-_{li wse o}

m_hl

i_tif

i_cnhr

g _{o a}

e_ns

x_{e p}

a_{m oarrt}

p_{l m of}

e_{so ar oeno}

f _ct

s_{aher group refers but is not limited urcbhon he atteormoasry cla,n in bcel replaced by furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazouldyel,: pyrrolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, p tyrriazolyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thienaoz[i3n,y2l-,} ^{-42- b te]fturarazonlyol,[1,5-a t]hpiyernidoi[n3y,2l,-b]t ihnidooplhyel,nyl i,ndoliz thinieynl,o[2 i,s3o-din]d[1o,3ly]lt,hiaz boelnyzl,ofura tnhyiel,no[ i2s,o3b-de]nimzoidfuarzaonlyyl, benziosthiophenyl, isobenzothiophenyl, indazol, benzimidazolyl, 1,3-benzoxazolyl, 1,2l benz ly -, 5 b beennzzooio}

t^sx

h^oa

i^athz

d^io

i^al

a^{zyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1- zoollyyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3- oxo-pyridazi l, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6- 1,3-benzodionx-1o(ly6lH, q)-uyiln,o 2lin-oyxl,o ipsyorqiduiinn-o1li(n2yHl,)- cyiln,no 6l-ionxyol,- qpuyrinidaazzoinlin-1y(l,6H qu)-inylo,xa 2l-ionxyol,p 7y-raidziani-n1d(o2lHyl),-y 6l-, 10 a Az}

s^unai

b^s“nod

t^itpo

u^tl

e^iyol

n^n,

t^{a 5}

s^{l-l (yaz}

f^{o sa}

r^uin

e^bd

x^so

a^til

m^tyul,

p^{te 4}

l^ed-a

1 ^hzeai

t^otned

4^rooaly

s^uryl.

b^{l”sti rteufeenrsts, to for a e hxeatmerpoleary 1l, h 2a,v 3in ogr optionally one or more defined above for substitu 4), selected from those T}

1^{5 iohdeo, te arsm w“ehlall aos” a onry“h sauloitgaetne}

l^e”d

i ^{a a}

s^slk

o^{t ayl}

o^{p g.}

e^{ro tuhp or part of a group is generic for fluoro, chloro, bromo, or W orh men b}

o^{e ereof.}

r^{eve hr the term“substituted” is used in the present invention, it is meant to indicate that one a selectionyd frroogmen ts on the atom indicated in the expression using“substituted” is replaced with exceeded, and thahte th inedi scuabted group, provided that the indicated atom’s normal valency is not that is sufficiently robust to ssutritvuition results in a chemically stable compound, i.e. a compound} _{20 a Wn}

a_nhd

d_{e f}

p_roerm

r_{e gferu}

r_ola

a_ut

b_pio

l_ysn

o _{m in}

n_ato

c_{y a}

e_{, b twe th}

i_{c oe}

e_{prat oipoe}

r_nu

t_hat

r_li ^v

l_c ^e i_{y a} ⁱ c_{e sn} ^{solation to a useful degree of purity from a reaction mixture,} ._ud

S_b/

u_so

b_{trist dui}

t_ita

t_eg

u_dn

e_,o

n_{t ss}

s_ut

m_{cich a}

a_{y ggre}

b_on

e_utp.

s_{esle mcateyd b freom su,b thstoitsuete ddef oinnecde a obro mvore, su}

2_{5 wsb ustsit e for A eudte hde arelkinyl. the terms such as“alkyl, aryl, or cycloalkyl, each being optiona}

a_{likthy”l, o oprti“oanlkayllly, a surybl,st oiturte cydc aloalkyl, optionally substituted with” refers to optionallllyy s suubbssttiittuutteedd More ge ryl and optionally substituted cycloalkyl.}

i_{nventionne mraaylly e,x from the above, it will be clear to the skilled person that the compounds of the geometrical isomisetr isn the form of different isomers and/or tautomers, including but not limited to 30 e sunbasnttiitoumenetrss o annd di dffiears,}

e_{te c}

n_rteo

p_on

o_ifso

s_{ormational isomers, E/Z-isomers, stereochemical isomers (i.e. itmioenrss) of an td isomers that correspond to the presence of the same such possible isomers, tautomers andhe m rixintugrses pre tsent in the compounds of the invention. All inventio hereof are included within the scope of the 35 t In additino.n, the invention includes isotopicall}

h_{oav cionmgp aonu antdosm oicf f moramsusla or (I m),a bsust n fourm tbheer f daicy}

f_{ft- e tl}

r_ha

e_ab

n_tel

t _{oled compounds and salts, which are identical frnoem o trh meo arteom aitcom msa are replaced by an atom commonly found in nature. Examples of isotopes that can be incorposrsat oerd m inatoss c noummpber most formula (I) are isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 11C, 13N,o 1u4Cnd,s 15 oOf} ^{-43- a tisnsdu 1e8F d.is Sturicbhut iisoonto apsicsaalylys-.la Fboerlle edxa cmomplpeou 11nCds a onfd fo 1r8mFu ilsao (tIo)p aerse u arseefu pl in drug and/or substrate (Positron Emission Tomography). PET is useful in brain imaarticularly useful in PET compounds of formula (I) can generally be prepared by car ging. Isotopically labeled 5 b laebloewle,d b rey substituting a readily available non-isotopically larbyienlegd ou reta thgeen ptro wcitehdu arnes iso ditsocpliocsaelldy Whenevera ugseendt.}

i^{s mea in the present invention the term“compounds of the invention” or a similar term al nt to include the compounds of general Formula I and any subgroup thereof. This term 10 h pys}

r^odo

-^{rda re}

r^tuefe

g^ss,rs

, ^{st t}

e^eo

s^{re th}

t^eoe

r^{iss c}

,^oomm

a^nep

d^riocu

m ^fnod

e^rtams

b^{s a}

o^,s

l^{i rta d}

e^ce

s^ep

,^mic

a^it

s^ced

w ^{m i}

e^{inxllt Tu araeb}

s^{sle ,}

t^{,h t 1}

e^{aiurt tohmeirer dicer fiovramtivse,s o,p Ntic-oaxli idseosm,e srasl,ts a,n saololvgauteess,, oxide forms of said compounds are meant to com quaternized nitrogen analogues. The N- nitrogen atoms are oxidized to the so-called N prise compounds wherein one or several 15 i As used in the specification and the appende-odxi cdlaei.ms, the singular forms "a",}

c^{nocmlupdoeun pdlu"ra mle raenferents unless the context clearly dictates otherwise. By way " oafn e",xa amndple "t,he "a"} T_h ^{s one compound or more than one compound.}

t_{hee a tret.rms described above and others used in the specification are well understood to those in 20 P Ar1e afenrdab Al2y, compounds of Formula I are defined as such that}

i_s

_{C, the anre selected from C and N; wherein when A1 is C, then A2 is N; and wherein when A2 Mor p f b Aly1 is A N i; N and A2 is C. Alternatively, A2 is N and A1 is C;}

2_{5 Pre (fCer=aObl)y-R, R1}

4_{, -( iCs= sSel)e-Rct4e,d -S frOo2m-R–4,H -,C–Nh,a -lNo,R -9O-SHO,2 --CR1-6}

4_{,a -Clk3y-6l,cy -Ocl-oCa1l-k6yall,k -yOl,- -CS3--C6c1y-6calolkayll, -NR9R10, - –Het1; wherein each of said -C1-6alkyl is optionally and independently kyl, -Ar1 and to 3 substituents selected from–halo, -OR35, -NR11R12, -O-C substituted with from 1 30 More preferably, R 1-6}

1 _{is selected from–H,–halo, and -C1 alkyl, and -S-C1-6alkyl.}

o _{Rp1t iison–ahlalylo a,n edve innd mepoerned pernetfleyra subblys Rtit1u itsed -6alkyl; wherein each of said C1-6alkyl is –F w.ith from 1 to 3–halo or -C1-6alkyl. More preferably Preferably, R5 is attached to Z1 or Z5 and is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-} ³⁵ ₆alkyl, -S-C_1-6alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈

6^{c ky} , -CN, -NR₆-SO₂-R₈, -C_{3- an} ^y

R_d ^clo

2_{3 iRn} ^a _d ^l

2_4e,p ^l

-_Oe ^, _n - -_Cd ^O _e- 1_-n ^C

6_at ³ _ly ^-6c

l_{ky s} ^y

l_u ^c

,_b ^lo

a_s ^a

n_tdi ^l _t ^k _u ^y

-_Ste ^l,

-_d ^-A

C_{1 w} ^r

-_6i ⁵

a_th ^an

l_{ky fr} ^d

l_o.m ^–H ₁ ^et _t ⁵ _o ^; ₃ ^wh _s ^e _u ^r _b ^e _s ⁱⁿ _titu ^e _e ^a _n ^c _t ^h _s ^o _s ^f _el ^s _e ^a _c ⁱ _t ^d _ed ^-C _fr ¹ _o ^-6 _m ^alk _– ^y _h ^l _a ^is _lo, ^op _-O ^tio _R ⁿ ₃ ^a _6, ^lly N _- ^{-44- Mor oept piorenfaelrlyab alny,d R in5d iesp seenledcetnetdly f sroumbs–titHu,te–dha wlioth, a frnod -C1-6alkyl; wherein each of said C1-6alkyl is R5 is selected from–H,–F, and a m m 1 to 3–halo, or -C1-6alkyl. More preferably 5 Prreefferably R ethyl group. Even more preferably, R5 is–H.}

P ^{5 is attached to Z1.}

s^{earaidbly -C,1 R2}

-^{6al iksy sle islec otpedtio fnroamlly - aHn,d -h ianldoe,p -eOnHd,en -Ctly1-6a slukbysl,t and -C3-6cycloalkyl; wherein each of selected from–halo,–OR27, and -NR13R14 ituted with from 1 to 3 substituents Mor aend pr aef mereatbhlyyl, g Rro2u isp. s Perleefceteradb flyro,m R2 - iHs– aHnd. A -.Clte1r-6naalktiyvle;ly m,o Rre2 preferably R2 is selected from -H 10 is a methyl group.}

P_{ref searaidbly -C,1 R3}

-_{6a ilsky sle ilsec otepdtio fnroamlly– aH}

n_n,

d_{d -h ialo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of selected from–halo, ndependently substituted with from 1 to 3 substituents 15 Mor aend pr aef mereatbhlyyl, g Rro3u isp. s Pe–}

r_leeO

f_cR

e_te2

r_ad8,

b _{f a}

l_{yro,m -N}

R_{3 - iHR1}

s_{– a5}

H_nRd16

. _{A -.Clte1r-6naalktiyvle;ly m,o Rre3 is pr aef mereatbhlyyl g Rr3ou isp s.elected from -H Pref -eSra-Cbly, R4 and R8 are each independently selected from–halo,–OH, -C1-6}

1_{-6alkyl alkyl, -O-C1-6alkyl, 20 MorOeH p,r oefre -rCa1b-6ly,}

a_{, - lk RN}

y_4R

l_{. i1s7R s1e8l,e -cCte3-d6c fyrocmloa–lkhyall,o -,O–-OCH3-6,c oyrcl -oCa1l-k6ayll,k -yAl;r4 an adnd R -8H iset s4.elected from–halo,– Pref Rer3a2,bl Ry,33 R,6 R,3 R7}

4_{,, R R9}

3_{5, a Rn1d0, R R11}

3_{6, a Rre12 e,a Rc1h3, i Rnd14e,p Re1n5d,e Rn1t6l,y R s1e7,le Rct1e8,d R f1ro9,m R2–0H, R,2 -1h,a Rlo2,2, = RO2,3, -O R2H4,, R -C31}

1_,- ²⁵ ₆

6^aalkyl, -O-C_1-6alkyl, -S-C_1-6alkyl, -C_3-6cycloalkyl, -Ar₆ and–Het₆; wherein each of said -C_1- –^{hlakylol, is–O opHti,o -nOa-lCly1- a6nadlky inl,d -eSp-eCn1d-6eanlktylyl, s -uCb3s-6tcituted with from 1 to 3 substituents selected from More preferably R6, R, R7,3 R9}

5 ^{a,n Rd1 R0,3 R11}

6 ^{ar,e R e1 ycloalkyl, -Het6, -Ar6 and–NR37R38.}

R ^{a2,ch R1 in3,d Rep14e,n Rd1e5n,t Rly16 s,e Rle1c7,te Rd18 f,ro Rm19,–H R,20 a,n Rd21 -,C R22}

1^{-6a,lk Ry2l3,, R24 31, R32, R33, R34 ,} _{30 Preferably, R27 and R28, are each independently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and More He}

p_{re pt}

f_r2

e_e.

r_{faebralybl Ry,27 R a2n7d a Rnd28 a Rr2e8 b aorteh e–aHc.h independently selected from–H and -C1-6alkyl, more 35 Preferably, R37 and R38, are each independently selected from–H, -halo, -OH, -C1-6alkyl, -O-C1- 6}alkyl, -S-C_1-6alkyl, -C_3-6cycloalkyl, -Ar₇ and–Het₇. ^{-45- More preferably, R37 and R38 are each independently selected from–H and -C1-6alkyl.}

P^ref

5 ^{-eNraRbly, X1 is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6}

3^{-C1-6alkyl-, -NR3-, -O alkyl-,} s _Su-Cbs1-t6it ^{-; wherein each of said -C1-6alkyl- is optionally and independently} a_{ultkeydl, w -pithhe fnryolm, 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, - More preferably, X1 is se and -NR33R34.}

s_{aid C1-6alkyl is optionallyle acntedd in frdoempe–nOde-Cnt1l-y6a slkuybl-s,ti NtuRte3d-C w1-i6tahlk fryol-m, - 1NR to3- 3, -–Oh-a;lo w,h -eOreHin, a enadch -C o1f-} ^{10 6alkyl.}

P^{ref -eNraRb2l-yC,1 X2}

-^{6al iksy slelected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, substituted wit-h, - fNroRm2-, 1 - tOo- 3; w shuebrsetiitnue enatcsh s oefle scateidd - fCro1m-6a–lkhyal-lo is, - oOpHti,on -Ca1ll-y6 and independently} _{15 S-C1-6alkyl,} ^{alkyl, -O-C1-6alkyl, -} M _{saoidre C p1r-6eafelkryalb ilsy -,p}

o _Xh

p_t2en

i_{o isyl}

n_{a s a}

l_en

l_yled

a_{c - ntNeddR3}

i_{n f1rR}

d_oem32.

p_{e–nOde-Cnt1l-y6a slkuybl-s,ti NtuRte2d-C w1-i6tahlk fryol-m, - 1NR to2- 3, -–Oh-a;lo w,h -eOreHin, a enadch -C o1f-} 6^{alkyl. 20 Pref cerably, Ar1, Ar4, Ar5, Ar6, and Ar7 ar}

A^{yrc4,le A orp5,tio Anra6lly comprising 1 to 3 heteer eoaactohm insd seepleecntdeedn ftrlyom a O 5-, N to a 1n0d-m Se;m eabcehre odf a saroidm Aatri1c, substituents, se alnedcte Adr7 f broeming– ohpatloio,na -OllyH, an -dC1 i-n6adlekpyle,nd -Oen-Ctly1-6a slukbysl,tit -uSte-Cd1- w6aitlhky from 1 to 3 wherein each of said -C1-6alkyl is optionally and independent l,–NR19R20; 25 moermeha ly substituted with from 1 to 3– M b plo}

e^rre.

e^{fder aarbolmy,a Aticr1 c,y Acrle4, o Aprt5io,n Aarl6ly, a conmdp Arris7in agre 1 e oarc 2h N in adteopmesn.dently selected from a 5- to 6-} P_{referably, Het1, Het2, Het4, Het5, Het}

3_{0 heterocycle having fr 6, and Het7 are each independently a 3- to 10-membered}

H _{toe 3t1, su Hbest2ti,tu H om 1 to 3 heteroatoms selected from O, N and S; wherein each of said eent4ts, H seelte5,ct Heedt6 f,ro amnd– Hhaelto7, is -O oHpt,io–nCa1l-l6yal aknydl, i -nOd-eCp1e-6nadlkeyntly substituted with from 1 C1-6alkyl, and -NR21R22; wherein each of said l, -S-C1-6alkyl, =O, -(C=O)- substituted with from 1 to 3–hal -C1-6alkyl is optionally and independently 35 M 3-o troe 6 p-mreefemrabbelrye,d H heet1t,er Hoecty2c,l Hee hta4,vi Ho}

n_e.

g_{t5 fr,o Hmet 16, to an 3d N H aetto7m asre. each independently selected from a} ^{-46- Pref ferably, Het8 is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected} w^ro

s_eh ^m

l_eerce ^O

t_ein ^{, N}

d _{s fa} ^a

r_oid ^nd

m _H ^S

–_e ^;

h_{t8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om -}

_{(C 1=O to)- 3C s1-u6ablstituents} 5 ⁶ _{kyl, -C1-} i^{nadlkeypl-eO-C1-6alkyl and -NR21R22; wherein each of said -C1-6alkyl i pti lly and More wh perreefeinnd}

r^{a we}

b^hn

l^yetl

,^ny

H ^{R su}

e^1b

t^{8 isst}

i^s–itHut

a^{,e td}

3^{h-e wnith}

t^{o a 1t fr}

0 ^leo

-^am

m^{set 1}

m ^{o tno}

b^{e 3}

e^{r h - eeh}

d^tael

h^roo;

e^{atetoromcy ocfle He hta8v isin agtta frcohmed 1 to to X23 hete 10 selected from O roatoms w seher}

n^ldece

i^ntein

d^{d s}

e^{p fra}

e^oid

n^{m H}

d^e–e,

h^{ta8 N}

l^{o is an}

,^{– od}

C^{p1t S}

-^i6o;

a^{nlkayllly, - aOn-dC i1n-6daelkpyel,nd =eOn;tl wyh seurbesintit euatecdh w ofith from 1 to 3 substituents a} _R ^nt ₁ ^{l said -C1-6alkyl is optionally} w_{herein when} ^y _is ^s _– ^u _H ^bs _, ^t _t ⁱ _h ^tu _e ^t _n ^ed _at ^w _le ^it _a ^h _s ^f _t ^ro _o ^m _ne ¹ _h ^t _e ^o _te ³ _ro ^-h _a ^a _to ^lo _m ^; _{of Het8 is attached to X2}

1_{5 M azoarbeic pyrcelfoe[r3a.b1l.y0,]h Heext8 is selected from piperazinyl, piperidinyl, pyrrolidinyl, pyrrolopiperazinyl, 3- octtraahhyyddrroopisyorrolo[1,2a-an]yply,razinyl, 2-a ozcatbaihcyydcrloo[-31.H1-.0p]yhreroxlaon[1y,l2,-a]pyraz 2i-nayzla,bic teyctrlaoh[2y.d2r.o1q]hueinpotalinnyyll, a te , sezalebcitceydcl foro[4quino}

m_{.1 linyl, morpholinyl, 3,4-dihydro-2H-benzo[6][1,4]oxazinyl, 2-oxa-5- 20 p.0y]rhreoplidtainnyyll,, p 1ip,e4r-aozxianzyel,p aanndyl, pip heormidoinpyipl.erazinyl. Even more preferably, Het8 is}

Vy pf bly Ht8 i l td f

_{h i h R i H th t l t} ^d _{ht t} ^;

2_{5 f Ht i tt hd t X} ^-47-

^More _wh ^pr _e ^e _r ^f _e ^e _in ^ra _w ^bl _h ^y _e ^, _n ^He _R ^t ₁ ⁸ _is ^is _– ^s _H ^e _, ^le _th ^ct _e ^e _n ^d _a ^fr _t ^o _le ^m _a

_{t ht t f Ht i tt h} ^; _{d to X2}

E^ven _wh ^m _e ^o _r ^r _e ^e _in ^p _w ^re _h ^fe _e ^r _n ^ab _R ^l ₁ ^y _i ^{Het8 is selected from}

^;

5 _{s–H, then at least on ht t f Ht i tt hd t X}

E^{ven wh meorreein p wrehfeernab Rl1y i Hse–tH8, is th}

^{t l t ne ; heteroatom of Het8 is attached to X2}

I_{n all the examplified Het8 groups above and below, the arrows indicates the attachment point.}

^{10 F grooru epx aanmdp tlhee, C}

^{means that the nitrogen atom is directly attached to the X2 Prefer b t t to it is directly attached to the X1 group.}

M^{ore parbelfye,r Za1b,ly Z,2 Z, Z1,3 Z, Z2,4 Z3,d Z4 Z a5nde Z e5a acrhe i enadcehpe Cn.dently selected from C and N.} _{15 I snter aeao p}

t_{eisarticular embodiment, the present invention provides compounds of Formula I or a solv tohmereero,f tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or} ^-48-

^{Wherein one or more of the foll}

^{ig I}

R^{1 is selected from–H,–halo, -OH ppli} 5 ^{(C=S)-R4 , -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, -} w _{suhbesrteitiune e} ^,

n_a - t_sc ^S _h ^O

s_{e o} ^{2 4}

l_ef ^-R

c _sta ^,

e_idd ^-C

f _-rC ^N

o_m1 ^, _-6 -_a ^N

–_lhk ^R

a_y ⁹ _l- l_{o i} ^S _s ^O

, _{- o} ²

O_p- R_t ^R _i3o ⁴

5_n ^,

,_a - -_l ^C _ly ^3- _a ^6c _n ^y _d ^cl _i ^o _n ^a _d ^l _e ^k _p ^y _e ^l, _n -_d ^O _e-_n ^C _tl ³ _y ^-6 _s ^c _u ^yc _b ^{loalkyl, -Ar1 and–Het1;} o_{NmR1–1RH1,2 stituted with from 1 to 3 R5 is attached to Z1 or Z5 and is selected fr ,– -hOa-loC,1- -6OalHky,l -,C a1n-6da -lkSy-lC,1 --O6a-lCky1-l6;alkyl, -S-C1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- ^{10 s 6cycl}

a^{unbdsotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteitiune enatsch se olefc staeidd f -rCom1-6a–lhkyallo is, - oOpRtio36n,a -lNlyR a23nRd24 in,d -Oep-Cen1-d6aelnktylyl, R2 is is se olpe -S}

t^ciot-eC

n^d1-6

a^{l flra}

y^olkmyl

a^n–;

d^{H i,n -dheapleo,n -dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanctsh o sf said -C1-6alkyl} _{15 sh salo,–OR27, and -N, -R13R} ^{elected from–} R _ise

a_{l ol}

o_pe

,_{tciotendal flryom an–dH indheapl14}

3 _{i eo,n -;}

d_{OeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanctsh o sfe sleacidte -dC f1-6alkyl h R–8O aRre28, e a rom– R ancdh - iNnRde15pRe1n6}

4 _{and d;ently selected from–halo,–}

Rⁿ _{OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} ^{20 R 6}

6^{, Ralkyl, -NR17R18, -C3-6cy}

R⁷

3^, _4, ^R _R ⁹

3^, ₅ ^R _a ¹ _n ⁰ _d ^{, R} _R ¹¹

3₆ ^, _a ^R _re ^12, _ea ^R _c ^1c

h^3l,oak

i_n ^Rl

d^14y

e^,l,

p ^{R -} e_n ^1O5 _d ^,-C

e ^R3-6

n¹ _t ^6c

l_y ^{,y Rc}

s_e ^1lo

l⁷ _e ^,a

c ^Rlk

t_e ^1y

d^{8l,, -} f ^RA

r_o ^1r4

m^{9, a}

–_H ^2d0 _, ^{, -} - ^RH

h_a ^2e1t4;

l^, _o, ^R ₌ ² _O ^2, _, ^R _-O ²³ _H ^{, R} _{, -} ² _C ^4, _1- ^R31

6_alk ^, _y ^R _l, ³ -² _O ^{, R} _-C ³³

1^,- 6 ^{oapltkioyln,a -llSy- aCn1d-6a inlkdyel,pe -Cnd3-e6cnytlcylo saulbkyslt,itu -tAerd6 w ainthd fr–oHmet 16; wherein each of said -C1-6alkyl is} 5 _R ^{–OH, -O-C} _1-6 ^{alkyl, -S-C} _1-6 ^{alkyl, -C} _3-6 ^{to 3 substituents selected from–halo,} _{2 R27 anndd R R28 are eaacchh i innddeeppeennddeennttllyy s seelle} ^c

e_c ^y

c_tte ^cl

e_d ^oa

d _{f fr} ^l

r_o ^k

o_m ^yl,

m_– ^-H

–_H ^e

H_, ^t

, _-6

-_C ^,

h₁ - a-^A _6loa ^r ₆

,_lk ^a

-_y ⁿ

O_l, ^d

H _-,C ^–

-₃ ^N

C_-6 ^R

1_c-6y37

a_c ^R

l_lko3

y_a8 ^;

l_{l,k -yOl- aCn1d-6 -aHlkeytl2 37 a 38 are e ,:}

y _{-S-C1- X is} ^6al _s ^k _e ^y _l ^l _e ^, _c ^-C _te ³ _d ^-6c _fro ^c _m ^loa _– ^lk _C ^{yl, -A} _k ^r7

1_-6alyl ^a _-, ^nd _–O ^–-^H _C ^e ₁ ^t7

1 _-6 ^; _{alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1- 30 s} ^{6alkyl-, -NR3-, and -O-; wherein eac} _n ^h _ts ^o _s ^f _el ^s _e ^a _c ⁱ _t ^d _ed ^-C _fr ¹ _o ^-6 _m ^alk _– ^y _h ^l- _a ⁱ _lo ^s _, ^o _-O ^pt _H ^io _, ⁿ -^a _C ^ll ₁ ^y _-6a ^a _l ⁿ

S_{u-Cbs1-t6itaultkeydl, w -pithhe fnryolm, a 1nd to -N 3R s3u3bRs3t4i;tue ky} ^d _l, ⁱⁿ _-O ^d-^e _C ^p ₁ ^e _-6 ⁿ _a ^d _l ^e _ky ⁿ _l ^t _, ^ly - ^-49- X_{2 is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2}

6^a _{-C1-6alkyl-, -NR2-C1-} s^{ulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C fr1o-6malk–yhl- is optionally and independently 5 S-C1 alo, -OH, -C1-6alkyl, -O-C1-6alkyl, - Ar -6}

1^{, o Aprti4o,a}

n ^Al

a^{lrkyl, -phenyl and -NR31R32;}

l^{5y, c Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle Ar5, Ar6, aonmdpr Aising 1 to 3 heteroatoms selected from O, N and S; each of said Ar1, Ar4, substituents selecr7t being optionally and independently substituted with from 1 to 3} w_{herein ea} ^{ed from–halo, -OH, -C} _1-6 ^{alkyl, -O-C} _1-6 ^{alkyl, -S-C} _1-6 ^{alkyl, and–NR} ₁₉ ^R ₂₀ ^; _{10 Het1h}

h_,a

a _{Hlo ch of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 - ve;}

i_{nt2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro inmde Op,e Nnd aenndtly S a; w 3h-e tore 1in0- emaechmb oefr seadid h Heteerocycle Het4, Het5, Het6, and Het7 is optionally and independently substituted with f t1, Het2,} ¹⁵ _{substituents selected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O,ro -}

_{(mC= 1O) t-oC13-} 6 ^{saulbksytl,itu atendd w -iNthR f2r1oRm221; t woherein each of said -C1-6alkyl is optionally and indp d tly Het8 a insd a 3- to 10-membered 3 he -htearloo;cycle having from 1 to 3 heteroatoms selected from O, N 20 s wher Se;in said Het8 is optionall}

-^{Oel-eCcted from–halo, -OH,–Cy1-6 aanlkdy iln,d -Cep1-e6anldkeylnetnlye, su -Cbs1-t6iatulkteydl-C w3i-t6hcy fcrolomalk 1y tl,o - 3C3 s-6ucbysctliotuaelknytsl, each1 o-6fa slkayidl, - -CS-C1-6alkyl, =O, -}

^{(Clly=O)-dC i1-6dalkpyl,d -Cen1-t6laylk syulb-Ost-iCtu1t-e6adlk wyilth an frdom -N 1R t2o1R 322}

1^{-6alkyl is optio -; wherein wherein when R1–H, then at l t ht tom of halo;} _{25 Z1, Z2, Z3, Z4 and Z5 are} ^{Het8 is attached to X2}

A_{1 and A2 are each indep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and I rn}

b_{aird p}

a_ica

d_art

i_clsicu

a_{ls tolar}

m _w,

a_{yh Xic1,}

b_{h a}

e _{p tnhd}

r_{eesy X2}

e _{anr a}

t_es

i_{n a u}

e_tts

i_ae

t_hcd

e_{hre h}

o_der

f _{b feoi}

o_rn

t_{m, r}

h _{d aep}

i_{re mre}

c_asce

t_iorn

n_ot

s_{cy b}

i_ncirla

t_ihcdi

e _pc

m_yarl

a_as,

c_{zo wlohpicyhrim taikdeinne to cogmetphoeurn wdi.th S tahied 30 a Rreefe prrreinfegrably present in the direction as described below: rocyclic pyrazolopyrimidine, but}

6 _X ^a _{1 i tso f soerlmecutlead I: from the list comprising *–C1-6alkyl-, *–O-C1-6alkyl-, *–S-C1-6alkyl-, *-C1-} a^{ttlakyclh-NedR t3o-C th1-e6a alkryyll- o,r *- hNeRte3r-oCa1r-6alkyl-, *-NR3-, *-O-; * wherein said biradical is preferably} _{35 X2 is selected from the list} ^C _c ¹ _o ^y _m ^{l m} _pr ^o _is ^ie _in ^ty _g ^v _* ^ia _–C ^*; _{1-6alkyl-, *–O-C1-6alkyl-, *–S-C1-6alkyl-, *-C1-} 6 _a ^a _tt ^l _a ^ky _c ^l _h ^-N _ed ^R _t ² _o ^-C _th ^1- _e ^6a _p ^lk _y ^y _r ^l _a ^-, _zo ^*- _lo ^N _p ^R _y ² _r-_imid ^-6 _i ^a _n ^l _e ^ky _m ^l-, _oi ^* _e-_t ^N _y ^R _v ² _ia ^-, _* ^* _; ^{-O-; * wherein said biradical is preferably -50- I snte a preferred embodiment, the present invention provides compounds of formula I or a s reoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or} 5 ^{Ro1lv isat}

( _wC ^se h₌ ^{e t} e_S ^lhee r_e) ^cr

-_inR ^{teeodf, fr wohmer–e} e_{ach ofR} ^{Hin,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6}

4_{, -SO2- s4a,id -C -CN, -NR9-SO2-R4, -C3-6cycloalkyl, -O-C3-6} ^{alkyl, -NR9R10, -(C=O)-R4, -} 1_{-6alkyl is optionally and independent cycloalkyl, -Ar1 and–Het1; substituents selected from–halo, -OR35, -NR11R12, -O-C1-6alkly substituted with from 1 to 3 R5 is attached to Z1 or Z5 and is selected from–H,–halo, -OH, -Cyl1,-6 aanlkdy -l,S --OCH1-6,a -lCky1-l6;alkyl, -O-C1-} ¹⁰ ₆alkyl, -S-C_1-6alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3- 6 ^{acnydclo inadlkeyple,n -dOe-nCt3ly-6c syucblosatiltkuytel,d -A wri5th an frdom–H 1et t5o; 3 wh seurbesintitu eeancths o sfel seacitded -C f1-6alkyl is optionally NR23R24, -O-C1-6alkyl, and rom–halo, -OR36, - R2 is selected from–H, -halo, - -OS-C1-6alkyl;}

i^{s optionally and indepe H, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl} _{15 halo,–OR27, and -NR13R} ⁿ ₁₄ ^d _; ^{ently substituted with from 1 to 3 substituents selected from–} R_{3 is is se olpetciotendal flryom an–dH i,n -dheapleo,n -dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanctsh o sfe sleacidte -dC f1r-o6alkyl halo,–OR28, and -N}

2⁰ _{nRde1 m– R R 5}

4 _{and 8 are each i pRe1n6}

o_d;

a_{ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R ⁶

6^{, Ra}

R^{7l,k Ryl9,, - RN1R17}

R^{0, RR18}

1^{1,, R -C3-6}

1^{2, Rc1y3c,l R14lk,y Rl,1 -5O, R-C3-6}

t_l ¹ _y ^6, _s ^Rcy

e¹ _l ^7c

e^,lo

c ^Ra

t_e ^1l

d^8k,y

f ^Rl,

r_o ^{1 -9A}

m^{, Rr4}

–^{2 a}

H^0,n

, ^Rd

-_h ^{2 -1H}

a^,e

l ^Rt4

o_, ^22;

=^, _O ^R _, ²³ -^, _O ^R _H ²⁴ _, ^, - ^R _C ³¹

3_{5 and 36 are each independen 1-} ^, _6a ^R _lk ³² _y ^, _l, ^R -³ _O ^{3 R} _-C ³⁴

1^,- 6 ^{oapltkioyln,a -llSy- aCn1d-6a inlkdyel,pe -Cnd3-e6cnytlcylo saulbkyslt,itu -tAerd6 w ainthd fr–oHmet 16; to w 3he sruebinstit euaecnhts o sfele sactided - fCro1-m6al–kyl is 25} _R ^{–OH, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38 halo,} 2_{7 an} ^;

R_{37 and R28, are each independently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2:}

C_{1d- R38, are each independently selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-} ³⁰ _{X s6}

1 _{is ealelkcytle,d -C f3r-o6cmyc–loCa1lk-6yall,k -yAl-r,7– aOnd-C–1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1- X} ⁶

2 _is ^al _s ^k _e ^y _l ^l _e ^-, _c -_te ^N _d ^R3 _f-_ro ^a _m ^nd _– ^– _C ^O ₁-_-6 ^; _{alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} A^{r 6}

1^,a

o ^Al

p^rk

t^i4y

o^{,l- n A, - alrN}

l^5y,R

c ^{A2- or,}

m^{6 a,n}

p^{r ad}

i^{sn - idO- ng A;}

1^{r7 to a 3re he etaecrhoa itnodmespe snedleecntetlyd f arom 5- O to, N 10 a-nmde Sm;b eearcehd o afr soamidat Aicr1 c,y Acle} _{35 A sur5b,st Aitr6, and Ar7 being optionally and independently substituted with from 1 to} ^r4 ₃ ^, w_{heruents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19R20; halo;ein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 -} ^{-51- Het1 h,a Hveint2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro independently a 3- to 10-membered heterocycle} H_et4 ^{m O, N and S; wherein each of said Het1, Het2, 5} _{subs,tit Hueetn5t,s H seetl6e,ct aendd fr Homet7– ihsal oop,t -ioOnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -}

_{(mC= 1O) t-o} 6^a _C13- s^{ulbksytl,itu atendd w -iNthR f2r1R22; wherein each of said -C1-6alkyl is optionally and indp d tly Het8 a insd a S 3;- to 10-meommbe 1re tod 3 he -htearloo;cycle having from 1 to 3 heteroatoms selected from O, N 10 w s e a s}

-^Oehl-er

C^ce

1^t-ein

6^{ad s}

l^{k fryoid}

l^{,m H}

-^S–e

-^ht

C^a8

1^{l i}

-^os

6^{a, o}

l ^-kOpt

y^{lHio p}

,^,n

=^O–aClly

,^{1 --}

^{(6 a}

C^{an ln}

=^lkd

O^{y i}

)^,d

-^{C -Ce1-e6 e}

1^-6aan

l^kldkyyl,lnet

-^nly

C^{e1-, su}

6^{a -Cb}

l^k1y-t6i

l^-atu

O^lkte

-^yd

C^{l-C w3i-t6hcy fcrolomalk 1y tl,o - 3C3 s-6ucbysctliotuaelknytsl, each of said -C 1-6}

1^{-6alkyl is optio lly d idp dently substituteadlk wyil and -NR21R22; wherein wherein when R1 is–H, then at t ht atom of Het8 is attacthhe fdro tmo X 12 to 3 -halo; 15 Z1 l}

A₁ ^{, a Zn2d, Z A3}

2^{, a Zr4e a enadc Zh5 in adreep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and} I _{snter aeo pisaortmiceurl,ar ta eumtobmoedri,m reanctem thice, p mreetsaebnotlit ien,ve pnroti-on or p prorevdidreusg, c soamlt,po huydnrdaste o,f N f-oorxmiduela f I or a 20 solvate thereof orm, or R1 is (C s}

h_=e

e_Sle

r_{e)c-inRte4d, e,a - fr w cSoh hOmer o2f-–e}

R_{Hin s4a,,}

i_{d -–Ch}

-_CNal

1_,o,

-_{6 -aN -O}

l_kRH

y_9l-,

i_{S - sOC1-6}

o_2p-tRa

i_o4l

n_,ky

a _-lCl,

l_{y3 --O}

a_{6c- nyC}

d_{c1l io-6}

n_{aallkkyyll,, - -SO--CC1-6}

3_{-6aclykcyllo,a -NlkRyl,9R -1A0r,1 -( aCn=dO)–-HRe4,t1 - w ; substituents selected from–halo, -OR35, -NR11R12, -dependently substituted with from 1 to 3} 25 _{R is attached to Z1 or Z5 and is selected from–H,–hOa-loC,1- -6OalHky,l}

O _{-,C a1n-6d}

2-R_{a - 8},_lkSy- -C_lC,1

3 _{-- -6O6}

5 _a

c_-l

y_Cky

cl₁o_-l6;

a_al_lk_ky_yl_l,_, - -O_S--_CC_{1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, - ^w(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-S _3- 6 ^{scuybcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; suhbesrteitiune enatsch se olefc staeidd f -rCom1-6a–lhkyal is optionally and independently and -S-C1- lo, -OR36, -NR23R24, -O-C1-6alkyl, 30 R s i kyl} h^{s se}

a ^{olpetciote 6}

2 ^{i ndal flra}

y^olkmyl

a^n–;

d^{H i,n -dheaploe,n -dOeHnt,l -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6al}

i_selo

o_lpe,

t_c–

i_otOendR ^{y substituted with from 1 to 3 substituents selected from–} R ₂

a_{l f7 , -R 4}

l_{ryo,m an}

a_n–d

d_{H -N}

i_ndh1

e_a3

3 _{is s plR}

e_o,1

n _-;

d_{OeHnt,ly -C s1u-6baslktiytul,te adnd -C3-6cycloalkyl; wherein each of said -C1-6alkyl 35 hal d with from 1 to 3 substituents selected from– R4 a} ⁶ _n ^a _do,

l^ky _R–

l^, _8O

-^N _aR

R_re28,

1⁷ _{e a}

R_an

1_c ^8, _{h -} -^O _iNnR

-_d ^C _e15

3_pR

-⁶ _e1

c^y _n6

c_d;

l_e ^o _n ^a _t ^l _l ^k _y ^yl _s ^, _e ^-C _le ³ _c ^-6 _te ^cy _d ^cl _f ^o _ro ^a _m ^lky _– ^l, _h ^-A _al ^r _o ⁴ _, ^a _– ⁿ _O ^d _H ^-H _{, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R^{6, R} _R ^{7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21,e Rt4}

2^{2;, R23, R24, R31, R32, R33, R34} 3₅

6alky _al,_nd -S _R-C₃₆

1_{- a6}a_relky _el,_ac -_hC_{3 in-6d}c_eyc_pl_eo_na_dlk_ey_nl,_tly -A _sr_e6le a_cn_ted_d– _frH_oe_mt₆;_–H w_,h -e_hr_ae_li_on_, e ₌a_Oc_,h _-O o_Hf_, s -a_Cid_1-6a -C_lk1y-6l,al -k_Oy-l_C i₁s- ^{-52- o–pOtHio,n -aOlly-C a1n-6dalk inydl,e -pSe-nCd1e-6natlklyyl s,u -Cbs3t-ituted with from 1 to 3 substituents selected from–halo, R 6cycloalkyl, -Het6, -Ar6 and–NR37}

2^{7 an R38;} 5 _{R an} ^d _d ^R _R ²⁸

3₈ ^, _, ^a _a ^r _r ^e _e ^e _e ^a _a ^c _c ^h _h ⁱⁿ _in ^d _d ^e _e ^p _p ^e _e ⁿ _n ^d _d ^e _e ⁿ _n ^tly _tly ^se _s ^l _e ^e _l ^c _e ^t _c ^e _t ^d _ed ^fro _fr ^m _om ^–H _– ^, _H -_, ^C -¹ _h ^-6 _a ^a _l ^l _o ^k _, ^y -^l, _O ^-C _H ³ _, ^-6 -^c _C ^y ₁ ^c _-6 ^l _a ^o _l ^a _k ^l _y ^k _l ^y _, ^l - ^a _O ⁿ-^d _C -₁ ^H _-6a ^e _l ^t _k ² 3_{7 y} ^: _{l, -S- X1 isC1 s-6ealelkcytle,d -C f3r-o6cmyc–loCa1lk-6yall,k -yAl-r,7– aOnd-C–1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,ut -eNdR w3-i,th a fnrdom -O 1-; to w 3h seurebisnt each of said -C1-6alkyl- is optionally and independently} S_{-C1-6alkyl, -phenyl, and -N} ^{ituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -} _{10 X R33R34}

2 _{is selected from–C1-6a} ^-; _lky ^w _l- ^h _, ^e _– ^re _O ⁱⁿ _-C ^e _1- ^a _6a ^ch _lky ^o _l- ^f _, ^s _– ^a _S ^id _-C -₁ ^C _{-6alkyl-, -C1-6alkyl-NR2-C1-6}

6^{alkyl-, -NR2-, and -O 1-6alkyl- is optiona} _{alkyl-, -NR2-C1-} s^{ubstituted with from 1 to 3 substituents selected from–halo, -OH, -Clly and independently S-C 1-6}

1^{-6alkyl, -phe alkyl, -O-C1-6alkyl, - Ar r4, Ar5, Ar6, andny Alr a7n adre -NR31}

1^{, A R32;}

1^{5 c Aormpriisnigng o 1pt tioon 3a hllyete arnoda etach independently a 5- to 10-membered aromatic cycle optionally ionmdes selected from O, N and S; each of said Ar1, Ar4}

7 ^{be , Ar5, Ar6, and} f_{rom–halo, -OH, -C1-6alkyl, -} ^{pendently substituted with from 1 to 3 substituents selected} C_{1-6alkyl is optionally and O-C1-6alkyl, -S-C1-6alkyl, and–NR19R20; wherein each of said - 20 Het1, Het2, Het4, Het5, Het6, an indd Hepeet7nd areent ely substituted with from 1 to 3 -halo;}

h _{Haevt4in,g H ferot5m, H 1e tto6, 3 a hnedte Hroeat7tom iss o spetiloencatea}

l_ldch

y _{fr ao independently a 3- to 10-membered heterocycle nmd O in, N and S; wherein each of said Het1, Het2, substituents selected from–halo, -OH,–C1-6alkydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -}

_{(mC= 1O) t-oC13-} 6

2^{5 saulbksytl,itu atnd -NR21R22; wherein each of said -C1-6alkyl is optionally and indp d tly Het8 is a bivaelden wti 3th- f troom 101-m toem 3}

O ^{b -hearelod; heterocycle having from 1 to 3 heteroatoms selected from wh,e Nre ainnd a St l;}

w^{herein wheenas Rt1 o inse– oHf, s tahiedn h aette leroaastto omnes i hse atettached to X1 or X2; 30 wherein said Het8 is optionally and independeronatltyom sub osft Het8 is attached to X2; and}

s _-O ^el-^e _C ^c ₁ ^t-^e _6a ^d _lk ^fr _y ^o _l, ^m _-S ^–-^h _C ^a ₁ ^l-^o _6a ^, _l -_k ^O _yl ^H _, ^, _=O ^–C _, ¹ --₍ ⁶ _C ^a ₌ ^lk _O ^yl ₎ ^{, -C1-6alkylene, -C1-6iatulkteydl-C w3i-t6hcy fcrolomalk 1y tl,o - 3C3 s-6ucbysctliotuaelknytsl,} , _{Z each of said -C}

_{-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and -NR21}

1_-6

2_{, Z3, Z4 and Z5 aarelky ela icsh o ipntdio R22; wherein Z1 epllyd dtly idlptdde fntly substituted with from 1 to 3 -halo; A1 and A2 are each independently rom C and N; and}

3_{5 selected from C and N.}

I _{snte a}

l_{vre f}

a_ou

t_eirsth

t_oe

h_mr

e_{re p}

e_ra

o_,r

f _tt

,_{aicuutolamre erm,b raocdeimmeicn,t m theeta pbreoslieten,t p inrvoe-n otiron pr perdorvuigd,es sa clot,m hpyodurantdes, o Nf- fooxrimdeula fo Iram o,r o a so r} ^-53-

^Wh

^Ia

R^{1 iesre} 5 ^{(C si}

=^en

S^{le)c-Rte4d, - frSoOm2-–RH4,, -–ChNal,o, -N -ORH9-,S -OC1-6}

2^{-alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, -} w_{herein each of said -C1-6alkyl is opt} ^R _io ⁴ _n ^, _a -_l ^C _ly ^3- _a ^6c _n ^y _d ^cl _i ^o _n ^a _d ^l _e ^k _p ^y _e ^l, _n -_d ^O _e-_n ^C _tl ³ _y ^-6 _s ^c _u ^yc _b ^l _s ^o _t ^a _it ^l _u ^k _t ^y _e ^l _d ^{, -} _w ^A _i ^r _th ¹ _f ^a _r ⁿ _o ^d _m ^– ₁ ^H _t ^e _o ^t1 ₃ ^; R_{5 is su abtstatictuheendts to se Zl1ec otred Z5 fro amnd– ihsa sloe,le -OctRed35, fr -oNmR1–1RH1,2,– -hOa-loC,1- -6OalHky,l -,C a1n-6da -lkSy-lC,1 --O6a-lCky1-l6;alkyl, -S-C1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- ^{10 6 scuybcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteitiune enatsch se olefc staeidd f -rCom1-6a–lhkyallo is, - oOpRtio36n,a -lNlyR a23nRd24 in,d -Oependently s an}

i^{s sed -C1-6alkyl, R2 i olpe -S}

t^ciot-eC

n^d1-6

a^{l flra}

y^olkmyl

a^{n–;H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl} _{15 ha 7} ^{d independently substituted with from 1 to 3 substituents selected from–} R _{s is selo}

o_lpe,

t_c–

i_otOendR2

a_{l flryo,m an}

a_n–d

d_{H -N}

i_{, -R}

n_dh1

e_a3

3 _{i lRo,14 -;OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl R halo,–OR28 pendently substituted with from 1 to 3 substituents selected from– 4 and R8 are, e aancdh - iNnRde15pRe1n6d;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} ^{20 R 6}

6^{, Ralkyl, -NR17R18, -C3-6cycloalkyl, -O}

R^{7, R9, R10, R11, R12} _a ^, _c ^R _h ¹³ _in ^, _d ^R _e ¹⁴ _p ^, _e ^R _n ¹ _d ⁵ _e ^, _n ^R-C3-6

t_l ¹ _y ^6, _s ^Rcy

e¹ _l ^7c

e^,lo

c ^Ra

t_e ^1l

d^8k,y

f ^Rl,

r_o ^{1 -9A}

m^{, Rr4}

–^{2 a}

H^0,n

, ^Rd

-_h ^{2 -1H}

a^,e

l ^Rt4

o_, ^22;

=^, _O ^R _, ²³ -^, _O ^R _H ²⁴

3_{5 and R36 are e ,} ^, - ^R _C ³¹

1-^, _6a ^R _lk ³² _y ^, _l, ^R -³ _O ^{3 R} _-C ³⁴

1^,- 6 ^{oapltkioyln,a -llSy- aCn1d-6a inlkdyel,pe -Cnd3-e6cnytlcylo saulbkyslt,itu -tAerd6 w ainthd fr–oHmet 16; to w 3he sruebins each of said -C1-6alkyl is} 5 ^{–OH, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycl tituents selected from–halo,} _{2 R R37 a anndd R R28}

3_{8,, a arree e eaacchh independently selecte} ^o _d ^a _f ^l _r ^k _o ^y _m ^{l, -} _– ^H _H ^e _, ^t6 _-C ^{, -} ₁ ^A _-6 ^r _a ⁶ _lk ^a _y ⁿ _l ^d _{, -} ^– _C ^N _3- ^R37

2_{7 6cy} ^R _cl ³ _o ⁸ _a ^; _{lkyl and -Het2: C1-6alkyl, -C3-6cyclo ianldkeylp,e -And}

l_-r,7ently

– _{a s–elected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S- X1 is selected from–C1-6alky Ond-C1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1- 30 s} ^{6alkyl-, -NR3-, and -O-; wherein eac} _n ^h _ts ^o _s ^f _el ^s _e ^a _c ⁱ _t ^d _ed ^-C _fr ¹ _o ^-6 _m ^alk _– ^y _h ^l- _a ⁱ _lo ^s _, ^o _-O ^pt _H ^io _, ⁿ -^a _C ^ll ₁ ^y _-6a ^a _l ⁿ

S_{u-Cbs1-t6itaultkeydl, w -pithhe fnryolm, a 1nd to -N 3R s3u3bRs3t4itue ky} ^d _l, ⁱⁿ _-O ^d-^e _C ^p ₁ ^e _-6 ⁿ _a ^d _l ^e _ky ⁿ _l ^t _, ^ly - ^-54- X_{2 is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2-C1-} 6 ^{saulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C f1-6alkyl- is optionally and independently 5 ,S-C1-6alkyl, -phe rom–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, - Ar nyl and -NR31R32}

1 ^;

o ^{Apr4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle Ationally comprising 1 to 3 heteroatoms selected from O, N and S; each of said Ar1, Ar4, sur5b,st Aitur6e,nt asn sdele Acr7ted be frinogm o–phtaiolon,a -lOlyH a,n -Cd} _1-6 ^{inadlkeypl,en -Ode-Cn} ₁ ^tl-^y ₆ ^{alk syulb,s -tSitu-Cte} ₁ ^d _-6 ^{al wkyitlh, a fnrodm–N 1R to 3} w_{herein each of said -C optionally and independently substitute 19}

1_{-6alkyl is} ^R ₂₀ ^; _{10 Het1h}

h_,a

a _{Hlo d with from 1 to 3 - ve;}

i_{nt2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro inmde Op,e Nnd aenndtly S a 3- to 10-membered heterocycle Het4, Het5, Het6, and Het7 is optionally and indepen ; wherein each of said Het1, Het2,} ¹⁵ _{substituents selected from–halo, -OH,–C1-6alkyl, -O-Cd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -}

_{(mC= 1O) t-oC13-} 6^{alkyl, and -NR21R22; wherein each o}

8 ^{substituted wit f said -C1-6alkyl is optionally and indp d tly Het h from 1 to 3 -halo;}

a ^{ins a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N 20 w}

- ^sOehd

l^{er S -eCce; 1t-ein}

6^{ad s}

l^{k faryoid}

l^{,m H}

-^S–e

-^ht

C^a8

1^{l i}

-^os

6^{a, o}

l ^-kOpt

y^lHio

,^,n

=^O–aClly

,^{1 --}

^{(6 a}

C^an

=^lkd

O^{y iln}

)^,d

-^{C -Cep1-e6}

1^-6aan

l^{kldkeylnetnlye, su -Cbs1-t6iatulkteydl-C w3i-t6hcy fcrolomalk 1y tl,o - 3C3 s-6ucbysctliotuaelknytsl, each of said -C1-6alkyl is optio l yl, -C1-6alkyl-O-C1-6alkyl and -NR21R22; wherein wherein when R1 is–H, then at llytd id hpt daetontly substituted with from 1 to 3 -halo; 25 Z m of Hetd8 i Ns. attached to X2}

1^{, Z2, Z3, Z4 and Z5 are each independently selected from C an}

P _A ^r ₁ ^e _a ^fe _n ^r _d ^ab _A ^l ₂ ^y, _a ^c _re ^om _se ^p _l ^o _e ^u _c ⁿ _t ^{ds of Formula Ia are defined as such that}

i_s

_{C p, thfen ed from C and N; wherein when A1 is C, then A2 is N; and wherein when A2 Mor b Aly1 is A N i;}

3_{0 N and A2 is C. Alternatively, A2 is N and A1 is C;}

P_{re(fCer=aObl)y-R, R1}

4_{, - is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, - –oH 3et s1u;b wshteitur(eC}

e_inn=S

t_{s e)a- scR}

e_h4,

l_{e o - cfS}

t_{e sO}

d_ai2

f_d-R

r_{o -mC4,1 - –-C6haN}

a_lk,

l_{oy - ,lN}

- _isR

O _{o9- RpStiOon2-aRll4y, a -Cn3d-6 icnydcelopaelnkdyel,n -tOly-C su3-b6csytictulotalkyl, -Ar1 and 35 t a35, -NR11R12, -O-C1-6alkyl, ed with from 1 Mor oept pisorenf}

–_ae

h_lr

a_lyab

l_{o al}

,_ny,

e_{d R}

v_{e in1}

n_{d i}

m_{esp s}

o_ee

r_nle

e_dc

p_et

r_ne

e_td

f_{ley fr}

r_{a soum}

b_blys–

R_tiHt1u,

i_tse–dh

–_{F wlo}

._{it,h a frnodm -C 11- t6oa 3lky–lh;a wlohe orrei -n a}

C_{1 en}

-_ad

6_{aclh -S}

k_{y o-C}

l_{.f M s1-a6a}

o_irdlk

e _{Cyl p1.}

r_{-e6afelkraylb ils R1 i y} ^-55- P_{referably, R5 is attached to Z1 or Z5 and is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1- 6}alkyl, -S-C_1-6alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3- 6 ^{acnydclo inadlkeyple,n -dOe-nCt3ly-6c syucblosatiltkuytel,d -A wri5th an frdo–Het5; wherein each of said -C1-6alkyl is optionally 5 Mor oeNR}

p^{t pior2e3R}

n^fae2

l^r4

l^{ya,b -O}

a^lny,-C

d ^R1-6

i^{n5d ia}

e^slk

p ^sy

e^el,

n^{le a}

d^cn

e^tned

t^{d -S m 1 to 3 substituents selected from–halo, -OR36, - ly f sr-oC}

u^m1-6

b^s–a

t^itHlk

u^,yl.

t^e–

y^dha

l ^wl

g^{riotoh, a}

u ^{fprnd -C1-6alkyl; wherein each of said C1-6alkyl is R5 is selected from–H,–F, and a meth o.m Ev 1en to m 3o–reha plroe,fe orra -bCly1-,6a Rlk5y isl.– MHo.re preferably 10 Preferably R5 is attached to Z1.}

P^{ref searaidbly -C,1 R2}

-^{6al iksy sle islec otpedtio fnroamlly - aHn,d -h ianldoe,p -eOnHd,en -Ctly1-6a slukbysl,tit auntedd -C w3i-t6hcy fcrloalkyl; wherein each of selected from–hal om 1 to 3 substituents More preferably, o,–OR27, and -NR13R14.}

1^{5 and a methyl g Rro2u isp. s Perleefceteradb flyro,m R2 - iHs– aHnd. A -Clte1r-6naalktiyvle;ly m,o Rre2 is pr aef mereatbhlyyl g Rr2ou isp s.elected from -H} P_{ref searaidbly -C,1 R3}

-_{6a ilsky sle ilsec otepdtio fnroamlly– aHn,d -h inadloe,p -eOnHd,en -Ctly1-6 saulkbysl,tit auntedd -C w3i-t6hcy fcrlooalkyl; wherein each of 20 selected from–halo m 1 to 3 substituents Mor aend pr aef mereatbhlyyl, g Rro3u is d}

p_{. s,}

P_e–

r_leeO

f_cR

e_te2

r_ad8,

b _{f a}

l_{yrno,m -N}

R_{3 - iHR1}

s_{– a5}

H_nRd16

. _{A -.Clte1r-6naalktiyvle;ly m,o Rre3 is pr aef mereatbhlyyl g Rr3ou isp s.elected from -H Preferably, R4 and R8 are each independently selected from–halo,–OH, -C1-6alkyl, -O-C 25 -S-C lkyl, -NR 1-6}

1_{-6a 17R18, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar alkyl, Mor OeH p,r oefre -rCa1b-6lya,lk Ryl. ted from–halo,–OH, or -C 4}

4 _{is selec 1-6alkyl; an adnd R -8H iset s4.elected from–halo,– Pref Rerably, R6, R7, R9, R10, R11, R12}

3_{2, R33, R34, R3 , R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31,}30 _{5 and R36 are each independently selected from–H,}e -in_ha e_loa_,c ₌h_{O, -OH C1- 6 1-} 6a

–^alkyl, -O-C_1-6alkyl, -S-C_1-6alkyl, -C_3-6cycloalkyl, -Ar₆ and–Het₆; wher of said_{, -} -C h^{lakylol, is–O opHti,o -nOa-lCly1- a6nadlky inl,d -eSp-eCn1d-6eanlktylyl, s -uCb3s-6tcityuctleodal wkith from 1 to 3 substituents selected from More preferably R6, R7, R9, R10, R11, R12, R13, R14, yl, -Het6, -Ar6 and–NR37R38.}

R _{, R} ^{R15, R16, R17, R18, R19, R20, R21, R22, R23} 1_{, R32, R33 34, R35 and R36 are e} ^{, R24} 3 ^, _{35 ach independently selected from–H, and -C1-6alkyl, Pref Hereatb2.ly, R27 and R28, are each independently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and} ^{-56- More pre pfreerfaebralybl Ry,27 R a2n7d a Rnd28 a Rr2e8 b aorteh e–aHc.h independently selected from–H and -C1-6alkyl, more}

⁵ _{Preferably, R37 and R38, are each independently selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-} M^{ore 6a plkryelf,e -rSa-bCly1,-6 Ral3k7y al,n -dC R3-6}

3^{8cy acreloa elakcyhl, i -nAdre7p aenndd–eHntelyt7 s.elected from–H and -C1-6alkyl.}

P^ref

1₀ ^{-eNraRb3l-yC,1 X1}

-^{6al iksy sl-e,le -NctRe3d-, fr -oOm-;– wCh1e-r6eailnky el-a,c–hO o-Cf1 s-a6aidlky -Cl-,1-–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-,} s _{Su-Cbs1-t6itaultkeyd with from 1 to 3 substituents selected from} ^6al _– ^k _h ^y _a ^l- _lo ^is _{, -} ^o _O ^p _H ^tio _, ⁿ _-C ^al ₁ ^l-^y _6a ^a _lk ⁿ _y ^d _l, ⁱⁿ _-O ^d-^e _C ^p ₁ ^e _-6 ⁿ _a ^d _l ^e _ky ⁿ _l ^t _, ^ly - _{M saoidre C p1r-6eafelkryalbl}

i_l,

s_{y -,p}

o _Xh

p_t1en

i_{o isyl}

n_{a s,}

l_{e a}

l_ylned

a_{cnt -eN}

d_dR

i_{n f3r3}

d_oR

e_m34.

p_{e–nOde-Cnt1l-y6a slkuybl-s,ti NtuRte3d-C w1-i6tahlk fryol-m, - 1NR to3- 3, -–Oh-a;lo w,h -eOreHin, a enadch -C o1f-} ^{15 6alkyl.}

P^{ref -eNraRb2l-yC,1 X2}

-^{6al iksy sl-e,le -NctRe2d-, fr -oOm-;– wCh1e-r6eailnky el-a,c–hO-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, substituted with from 1 of said -C1-6alkyl- is optionally and independently} S_-C ^{to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -} _{20 M saoidre C pr1e-6fearlkaybll,y -,p Xh}

p_t2en

i_{o isyl}

n_{a s a}

l_en

l_yled

a_{c - ntNeddR3}

i_{n f1rR}

d_oem32.

p_{e–nOde-Cnt1l-y6}

1_{-6alkyl is o a slkuybl-s,ti NtuRte2d-C w1-i6tahlk fryol-m, - 1NR to2- 3, -–Oh-a;lo w,h -eOreHin, a enadch -C o1f-} 6^{alkyl. 25 Pref cerably, Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to}

A^{yrc4,le A orp5,tio Anra6,lly an codm Aprr7is binegin 1g to op 3ti hoentaellryoa atonms selected from O, N a 1n0d-m Se;m eabcehre odf a saroidm Aatri1c, substituents sele scatiedd -C f1r-o6amlky–lh isal d independently substituted with from 1 to 3 wherein each of oop,tio -OnaHl,ly - aCn1d-6a inlkdyelp,e -nOd-eCn1t-l6ya slkuybl,sti -tSut-eCd1-6 wailtkhy fl,rom–N 1R t1o9R20;} _{30 moerme} ^{ha 3–} M _{b p} ^lo

e_rre ^.

e_{fder aarbolmy,a Aticr1 c,y Acrle4, o Aprt5io,n Aarl6ly, a conmdp Arris7in agre 1 e oarc 2h N in adteopmesn.dently selected from a 5- to 6- Preferably, Het1, Het2, Het4, Het5, Het6, and Het7 are each independ}

3_{5 heterocycle having from 1 to 3 heteroatoms selected ently a 3- to 10-membered}

H _{toe 3t1, su Hbest2ti,tu Heent4ts, H seelte5,ct Heedt6 f,ro amnd– Hhaelto7, is -O oHpt from O, N and S; wherein each of said}

,_{io–nCa1l-l6yal aknydl, i -nOd-eCp1e-6nadlkeynl,tl -yS s-Cub1-s6taitlukytel,d = wOit,h -( fCro=mO) 1-} ^{-57- C su1b-6salkyl, and -NR21R22; wherein each of said -C1-6alkyl is optionally and independe 3- to 6-met}

e^fietu

m^rate

b^bd

e^{lry w}

e^,i

d ^{Hth om ntly More pr heet f1r}

t^{,er Hoe 1}

c^{ty2 t}

c^,o

l ^{H 3}

e^{e ht–}

a^4h,a

v^{i Hlo}

n^e.

g^{t5 fr,o Hmet 16, to an 3d N H aetto7 are each independently selected from a 5 ms.}

P_{ref ferroambly, Het8 is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selec selece O}

t_{ein, ted wher N}

d _{s fa a}

r_oidnd

m _{H S}

–_e;

h_{t8a ilso, o -pOtiHon,a–llCy1 a-6nadlky inl,de -Ope-Cnd1-e6anltklyyl, su -Sbs-Ctit1u-6taeldky wl,ith =O fr,om - 1 to 3 substituents} ¹⁰ _{(C=O)-C1-6alkyl, -C1-} 6 ^{inadlkeypl-eOn-dCe1n-6talylk syulbs atnitdute -dN wRi2th1R22; wherein each of said -C1-6alkyl i pti lly and wherein when R1 is–H, then at fr leoamst 1 o tnoe 3}

h ^{-ehtaelroo;atom of Het8 is attached to X2 15 Maar}

o^zo

c_ta ^be

h^{ic p}

y^yr

d^ce

r_o ^lfoe3a

p^[r

y_r ^{.b1l xt}

r_o ^.y0,

l_o ^{]h H}

[₁ ^ee

,₂ ^a8

-_a ^{n is}

]^{yl s,elected 2 f-raozmab piicpyecrlaoz[3in.1y.l,0 p]hipeexraidniynl,yl, pyrrol 2id-ainzyal,bi pcyyrcrlool[o2p.2ip.e1r]hazeipntyaln,y 3l-,} t_{etarahydro pyrazinyl, octahydro-1H-pyrrolo[1,2-a]pyrazinyl, tetrahydroquinolinyl, azebicy isoquinolinyl, morpholinyl, 3,4-dihydro-2H-benzo[6][1,4]oxazinyl, 2-oxa-5- sel clo[4.1.0]heptanyl, 1,4-oxazepanyl, homopiperazinyl. Even more preferably, Het8 is 20 wctheedre frionm w phyernro Rli1di insy–l,H p,ip theeranz ainty lel,a asntd on peip heeritdeirnoyal;tom of Het8 is attached to X2}

Vy pf bly Ht8 i l td f

_{h i h R i H th t l t} ^d _{ht t} ^;

2_{5 f Ht i tt hd t X} ^-58-

^More _wh ^p _e ^re _re ^fe _in ^ra _w ^bl _h ^y _e ^, _n ^H _R ^et ₁ ⁸ _is ^is _– ^s _H ^e _, ^le _th ^ct _e ^e _n ^d _a ^fr _t ^o _le ^m _a

_{t ht t f Ht i tt hd to X2}

₅ ^Even _wh ^m _e ^o _r ^r _e ^e _in ^p _w ^re _h ^fe _e ^r _n ^a _R ^bl ₁ ^y _i ^H _s ^e _– ^t _H ⁸ _, ^is _th ^s _e ^e _n ^le _a ^c _t ^t _l ^e _e ^d _as ^fr _t ^o _o ^m _n

_{ht t f Ht i tt hd t X} ^;

^{Even wh meorreein p wrehfeerna Rbl1y i Hse–tH8, is th}

^{t l t ne ; heteroatom of Het8 is attached to X2}

1^{0 P Mroerfeer parbelfye,r Za1b,ly Z,2 Z, Z1,3 Z, Z2,4 Z a3n,d Z4 Z a5n adre Z e5a acrhe i enadcehp Cen.dently selected from C and N.} I _{snte are fouirsthoemre pra,r ttaicuutolamre erm,b raocdeim}

l_{vate thereof, meicn,t m theeta pbreoslieten,t p inrvoe-n otiron pr perdorvuigd,es sa clot,m hpyodurantdes, o Nf- fooxrimdeula fo Iram o,r o a 15 so r}

Ia ^{-59- W R1h iesre}

(^{C si}

=^en

S^{le o}

)^cn

-^{Rteed or fr momore–H of, t–h}

C^he

N^{a flo}

,^ol,lo

-^{N -wOin}

R^{Hg, a -Cp1p-l6iaelsk:yl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4 4, -SO2-R4, - 9-SO2-R4, -C3-6c , -} 5 _{wherein each of said -C1-6alkyl is optionally an} ^y _d ^{cloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1;} R _{is su abtstatictuheendts to se Zl1ec otred Z5 fro amnd– ihsa sloe,le -OctRed35, fr -oNmR1–1RH1,2 i,n}

– _-d

h_{Oependently substituted with from 1 to 3 a-loC,1- -6OalHky,l -,C a1n-6da -lkSy-lC,1 --O6}

5 _{a-lCky1-l6;alkyl, -S-C1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- 6 ^{scuybcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteitiune enatsch se olefc staeidd f -rCom1-6a–lhkyallo is, - oOpRtio36n,a -lNlyR a23nRd independently 10 R2 is an}

i^{s sed}

o^{l -S-C 24}

1^{-6alkyl; , -O-C1-6alkyl, petciotendal flryom an–dH i,n -dheapleo,n -dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoycloalkyl; wherein each of said -C1-6alkyl} i_{halo,–OR27,} ^{m 1 to 3 substituents selected from–} _{15 R s i hs se}

a_{l ol}

o_pe

,_tc

–_iote

O_nd

R_{al flryom an}

a_n–d

d_{H -N}

i_{,n -R}

d_h1

e_a3

p_lR

e_o,14

3 _{n -;}

d_{OeHnt,l -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl e28, y substituted with from 1 to 3 substituents selected from– R nd R e aancdh - iNnRde15pRe1n6}

4 _{a 8 ar d;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- 20} ^{R 6alkyl, -NR17R18}

6^{, R}7^{, R}9^{, R}10^{, R}11^{,, R -C3-6}

12^{, Rc}1^y3^{c,lo Ra}14^{lk,y Rl,}1 -5^{O,-C3-6cycloalkyl, -Ar4 and -Het4;}

R ^{6alkyl, -S-C1-6alky} _e ^l, _ac -_h ^C3 _in ^-6 _d ^c _e ^yc _p ^l _e ^o _n ^a _d ^lk _e ^y _n ^R

l^, _tl1_y6^,

-^A _s ^R

r_e1

6_l7_e ^, _c ^R _te1_d8^, _f ^R _ro19_m ^{, R} _–2_H0^, _, ^R _-h21_a ^, _l ^R _o,22 ₌ ^, _O ^R _,23 -^, _O ^R _H24_, ^, - ^R _C31

1-^, _6a ^R _lk32 3_{5 and R36 are y} ^, _l, ^R -3_O3 ^R _-C34

1^,- o^{ptionally and independently substituted w ainthd fr–oHmet6; wherein each of said -C1-6alkyl is –OH, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -He 1 to 3 substituents selected from–halo,} R_{27 and R28, are each independently selected from–H,} ^t6 _-C ^{, -} ₁ ^A _-6 ^r _a ⁶ _lk ^a _y ⁿ _l ^d _{, -} ^– _C ^N _3- ^R37

6_cy ^R _c ^38;

2_{5 R37 a Cn1d-6a Rlk3y8,l, a -Cre3-6 ecaycchlo ianldkeypendently selected from–H, -halo, -OH, -C1-6laolaklykly,l - aOn-dC -1H-6aeltk2y:l, -S- X1 is selected from–C1-6all,k -yAl-r,7– aOnd-C–1H-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,ut -eNdR w3-i,th a fnrdom -O 1-; to w 3h seurebisn each of said -C1-6alkyl- is optionally and independently} _{30 X2 isS- sCe1l-e6acltkeydl, f -rpohmen–yCl,1 a-6nadlk -yNl-R,3–3R} ^{tituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -} O_{3-4C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2-C1-} 6 ^{saulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C fr1o-6malk–yhl-al ios, o -OptHio,n -aCll1y-6a alknydl, i -nOd-eCp1e-6nadlently 35 S-C}

o_p ^r1-6

t_i4_o ^,a

n ^Al

a_l ^rk

l5^y

y^,l,

c ^{A -p}

o^r _m6^{h kyl, - Ar ,e}

p_r ^an

i_s ^ny

i^{dl an}

n_g ^Ad

1^r7 ^-N

t_o ^aR

3^re31

1^{, A R}

h_e ^e3

t^a2

e^c;

r^h _oa ⁱ _t ⁿ _o ^d _m ^e _s ^pe _s ⁿ _e ^d _le ^e _c ⁿ _te ^tly _{d f} ^a _rom ^5- _O ^to _{, N} ¹⁰ _a-_n ^m _d ^e _S ^m _; ^b _e ^e _a ^{red aromatic cycle} A_{r Ar6, and Ar7 being optionally and independently substituted wchith of f sroamid A 1r1 5, , to Ar4, substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19R203;} ^{-60- whahleorein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 - Het1} _h ^, _a ^H _v ^e;

i_n ^t2 _g ^{, H} _fro ^e _m ^t4, ₁ ^H _t ^e _o ^t5 ₃ ^{, H} _h ^e _e ^t _t ⁶ _e ^, _r ^a _oa ⁿ _t ^d _om ^He _s ^t7 _se ^a _l ^r _e ^e _ct ^e _e ^a _d ^ch _fro ⁱⁿ _m ^de _O ^p _, ^e _N ^nd _a ^e _n ⁿ _d ^tly _S ^a _{; w} ³ _h-_e ^to _re ¹ _in ^0- _e ^m _a ^e _ch ^mb _o ^e _f ^r _s ^e _a ^d _id ^h _H ^et _e ^e _t ^r ₁ ^o _, ^c _H ^y _e ^cle 5 _{H suet4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 tot23, bstituents selected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

_(C=O)-C1- 6 ^{saulbksytl,i and -NR21R22; wherein each of said -C1-6alkyl is optionally and indp d tly 10 Het8 a ins a 3tu-te tod 1 w0it-hm ferommbe 1re tod 3 he -htearloo;cycle having from 1 to 3 heteroatoms selected from O, N w sehd}

l^{eer S}

c^e;

t^{eind s faroidm H–ehta8l ios, o -OptHio,n–aClly1-6 aanlkdy iln,d -Cep1-e6anldkeylnetnlye, su -Cbs1-t6iatulkted with from 1 to 3 substituents -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

^{(C=O)-C1-6alkyl yl-C3-6cycloalkyl, -C3-6cycloalkyl, 15 each of said -C1-6alkyl is optio lly d idp,d -Cen1-6alkyl-O-C1-6alkyl and -NR21R22; wherein Z wherein when R1 is–H, then at l t ht atomtly o sfu Hbestti8tu iste adtt wacithhe fdro tmo X 12 to 3 -halo; 1, Z2, Z3, Z4 and Z5 are each independently selected from C and N.}

I _{snte arenooitshoemre pra,rt tiacuutlar embodiment the present invention provides compounds of formula Ia or a 20 s Ro1lv isat}

(_{C se}

=_{e t}

S_lhee

)_cr

-_{Rteeodf, omer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or fr wohmer–eHin,–halo, -ORH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9}

4_{, -SO2-R4, -CN, -N9-SO2-R4, -C3-6cycloalkyl, -O-C3-6cycloa R10, -(C=O)-R4, - wherein each of said -C1-6alkyl is optionally and independently substilkyl, -Ar1 and–Het1; 25 substituents selected from–halo, -OR35, -NR11R12, -O-C1-6alkyl, and -tuted with from 1 to 3 R5 is att}y_al,_ch -N_edR _{to Z1 or Z5 and i} -_s(C _s=_eS_le)_c-R_{ted from–H,–halo, -OH, -C1-6alkSy-lC,1 --O6a}

c_-l

y_Cky

cl₁o_-l6;

6alk ₆R₇, -(C=O)-R₈, ₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6 a_al_lk_k

6^c y_yl_l,_, - -O_S--_CC_{1- 3-} s^{uybcslotitaulkteydl, w -Aitrh5 f aronmd– 1H teot53; w suhbesrteitiune enatsch se olefc staeidd f -rCom1-6a–lhkyallo is, - oOpRtio36n,a -lNly and independently} _{30 s an}

6^a _sd

l^k _e ^y _{l -eS}

l ⁱ _c- s_tCe1

o_d- ^{R23R24, -O-C1-6alkyl,} R ₆

2 _{i a}

p^t _f ⁱ _rl

o_ok

n_myl;

a^lly _–H ^a _, ^nd _-h ⁱ _a ⁿ _l ^d _o ^e _, ^p -^e _O ⁿ _H ^d _, ^en _-C ^tly _1-6 ^s _a ^u _lk ^b _y ^s _{l, and -C3-6cycloalkyl,; wherein each of said -C1-} –^{halo,–OR27, and - tituted with from 1 to 3 substituents selected from R is selected NR13R14}

3 ^; _{35 option} ^{from–H, -halo, -OH, -C1-6alkyl, -C3-6cycloalkyl; wherein each of said -C1-6alky} _o ^l _, ⁱ _– ^s R _{OR28 R,ally and independently substituted with from 1 to 3 substituents selected from–hal}

8 _{an adre -N eRa1c5hR1 in6}

4 _{and ;dependently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R ⁶

6^{, Ralkyl, -NR17R18, -C3-6cycloalkyl, -O-C3-6cycloalk1yl, -Ar4 and -Het4;}

R⁷

3^, _4, ^R _R ⁹

3^, ₅ ^R _a ¹ _n ⁰ _d ^{, R} _R ¹¹

3₆ ^, _a ^R _re ^12, _ea ^R _c ¹ _h ^3, _in ^R _d ¹⁴ _e ^, _p ^R _en ¹⁵ _d ^, _e ^R _n ¹ _t ⁶ _ly ^{, R} _se ¹ _l ⁷ _e ^, _c ^R _ted ^8, _f ^R _ro ¹ _m ^{9, R} _–H ²⁰ _, ^, - ^R _ha ²¹ _l ^, _o, ^R ₌ ² _O ^2, _, ^R _-O ²³ _H ^{, R} _{, -} ² _C ^4, _1- ^R31

6_alk ^, _y ^R _l, ³ -² _O ^{, R} _-C ³³

1^,- ^{-61- 6 oapltkioyln,a -llSy- aCn1d-6a inlkdyel,pe -Cnd3-e6cnytlcylo saulbkyslt,itu -tAerd6 w ainthd fr–oHmet 16; to w 3he sruebinstit euaecnhts o sfele sactided - fCr1-6alkyl is –OH, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38; om–halo,} 5 _{R R27}

3_{7 a and R28, are each independently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -He}

C_{n1d-6a Rlk3y8,l, a -Cre3-6 ecaycchlo ianldkeylp,e -Andently selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6altk2y:l, -S- X s selected from–C1-6alkyl-r,7– aOnd-C–1H-6aeltk7}

1 _{i ;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} ¹⁰ _X ⁶

2 _is ^al _s ^k _e ^y _l ^l _e ^-, _c -_te ^N _d ^R3 _f-_ro ^a _m ^nd _– ^– _C ^O ₁-_-6 ^; _{alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} A^{r 6}

1^,a

o ^Al

p^rk

t^i4y

o^{,l- n A, - alrN}

l^5y,R

c ^{A2- or,}

m^{6 a,n}

p^{r ad}

i^{sn - idO- ng A;}

1^{r7 to a 3re he etaecrhoa itnodmespe snedleecnttly a 5- to 10-membered aromatic cycle Ar5, Ar6, and Ar7 being optionally and indeepden frdoemntl O, N and S; each of said Ar1, Ar4, substituents selected from–halo, -OH, -C1-6alkyl, -O-yC1 s-6uabstituted with from 1 to 3 15 wherein each of said -C1-6alkyl is optionally and indepen lkyl, -S-C1-6alkyl,–NR19R20;} e_{t1 h} ^{dently substituted with from 1 to 3 -} H _h,a

a _Hlo

v_e;

i_{nt2g, H froemt4, 1 H teot53, H heett6e,r aoantdom Hest7 se alreect eeadch fro inmde Opendently a 3- to 10-membered heterocycle Het4, Het5, Het6, and Het7 is optionally and in,d Nep aend S; wherein each of said Het1, Het2, 20 s} ^6a _u ^l _b ^k _s ^y _t ^l, _itu ^a _e ⁿ _n ^d _ts - _s ^N _e ^R _le ² _c ¹ _t ^R _e ² _d ^2; _fro ^w _m ^he _– ^re _h ⁱ _a ⁿ _lo ^e _, ^a _-O ^ch _H, ^o _– ^f _C ^s ₁ ^a _-6 ⁱ _a ^d _lky -_{l, -O-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6taedlky wl,it =hO f,ro -}

_{(mC= 1O) t-oC13-} s^{ubsti C1-6alkyl is optionally and indp d tly Het8 is a 3tu-te tod 1 w0it-hm from 1 to 3 -halo; 25 and S embered heterocycle having from 1 to 3 heteroatoms selected from O, N w sehleerce;}

t^ein

-^{O d s faroidm H–ehta8l ios, o -OptHio,n–aClly1-6 aanlkdy iln,d -Cep1-e6anldkeylnetnlye, su -Cbs1-t6iatulkteydl-C w3i-t6hcy fcrolomalk 1y tl,o - 3C3 s-6ucbysctliotuaelknyts ea-C1-6alkyl, -S-C1-6alkyl, =O, -(C=O)-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and -NR2 l, whcehre oinf s wahiden -C R o}

1 ^{is–H lly d idp dently substituted with from 1 to1}

1^{-6alkyl is opti R 322 -;h wherein} _{30 ac} ^, _h ^th _i ^e _n ⁿ _de ^a _p ^t _e ^l _nde ^t _{ntly s} ^h _ele ^t _cted ^at _f ^o _ro ^m _m ^o _C ^{f alo;}

Z ^H _a ^e _n ^t _d ^{8 i} _N ^s _. ^{attached to X2}

1_{, Z2, Z3, Z4 and Z5 are e}

I _{snte arenooitshoemre pra,rt ti}

,_acu

w_uhtlaor

e_{m e}

r_eem

i_{nr,b roadciemmeinct, t mheet parbeosleitnt invention provides compounds of formula Ia or a 35 solvate thereof e, pro- or predrug, salt, hydrate, N-oxide form, or R1 is (C s=eSle)c-Rte4d, - frSoOm2-–RH4,, -–ChNal,o, -N -ORH9-,S -OC1-6}

2_{-Ra4l,ky -Cl,3 --O6c-yCc1lo-6aallkkyyll,, - -SO--CC1-6}

3_{-6aclykcyllo,a -NlkRyl,9R -1A0r,1 -( aCn=dO)–-HRe4,t - whbesrteitiune enatsch se olefc staeidd f -rCom–halo, -OR35, -NllyR a11nRd12 i,n -dOe-pCe1n-6daelknytlly, a snudbs -Stit-uCte1-d6a wlkiythl; from 1 to1}

1_{-6alkyl is optiona 3; su} ^-62- R_{5 is attached to Z1 or Z5 and is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- 6

5 ^{scuycloalkyl, -Ar5 and–Het5; wherein each of said -C1-6alkyl is optionally and independently R2 is anbdstituted with from 1 to 3 substituents selected from–halo, -OR36, -NR23R24, -O-C1-6alkyl, is se olpe -S}

t^ciot-eC6

n^{d1- al flra}

y^olkmyl

a^n–;

d^{H i,n -dheapleo,n -dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanctsh o sf said -C1-6alkyl} h_alo

1_{0 i hsal ol}

o_{pe, ,tc– –iotOe}

O_ndR ^{elected from–} R ₂

a_{l f7}

l_{ryo,m an}

a_n–d

d_{H -N}

i_{,n -R}

d_h1

e_a3

3 _{is se plR -;}

e_o,14

n_{dOeHnt,ly -C s1u-6baslktiytul,te adnd w -iCth3-6 frcoymclo 1alk toyl; 3 w shuebrsetinitu eeanctsh o sfe sleacidte -dC f1r-o6amlky–l R 7, R9, RR28}

1_{0,, R a1n1d, - RN1R15}

6_{, R 2, RR16}

1_3,;

i_{ndependently selected from R–H14,, R -h1a5,lo R,1 =6,O R,19 -,O RH2,0, - RC21}

1_{-6,a Rlk2y2l,, R -O31-,C R32}

1_{-6a,l Rky3l3, a -nSd-C R34}

1_{-6a alkryel, e -aCc3h-} ^{15 6 sc}

C^{uybcslotitaulk}

o^tey

a^dl,

l^{k w -A}

y^li,thr6

-^{H f a}

e^ron

t^{md 1–H toet 36; s wuhbesrtietuinen etsac shele ocfte sadid fro -mC1-–6halaklyol, i–sO oHp,ti -oOn-aCll1y-6a alnkydl, in -Sd-eCp1e-6ndently 3-6cycl 6, -Ar6 and– alkyl, -} R _R7

3_{7 a anndd R R28}

3_{8,, a arree e eaacchh in inddeep} ^R

p_eennd ^N

d_een ^R

n_t ³ _ly ⁷

t_{ly s} ³ _e ⁸

2 _sl ^;

e_{elcetcetded fro frmom–H–,H -,C -1h-6aallok,y -l,O -CH3,-6 -cCy1c-6laolaklykly,l - aOn-dC -1H-6aeltk2: 20 C1-6alkyl, -C3-6cycloalkyl, -Ar7 and–H yl, -S- X1 is selected from–C1-6alkyl-,–O-C1-6aeltk7;yl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,ut -eNdR w3-i,th a fnrdom -O 1-; to w 3h seurebisntit euaecnh of said -C1-6alkyl- is optionally and independently} S_-C ^{ts selected from–halo, -OH, -C1-6alkyl, -O-C1-6}

1_-6alkyl, ^{alkyl, - 25} _{X -phenyl, and -NR33R34}

2 _{is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2-C1-} 6 ^{saulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C fr1o-6malk–yhl-al ios, o -OptHio,n -aCll1y-6a alknydl, i -nOd-eCp1e-6nadlkeyntly S-C1}

o^ptio,-6a

n ^Al

a^lrk

l^5y

y^,l,

c ^{A -p}

o^rm6h,e

p^{r an l, - Ar1, Ar4 isny}

i^{dl an}

n^{g Ad}

1^{r7 -N}

t^{o aR}

3^re31R

h^{e e3}

t^a2

e^c;

r^{hoa itnodmespe snedleecntetlyd f arom 5- O to, N 10 a-nmde Sm;b eearcehd o aromatic cycle 30 A sur5b,st Aitur6e,nt asn sdele Acr7ted be frinogm o–phtaiolon,a -lOlyH a,n -Cd1-6 inadlkeypl,en -Ode-Cn1tl-y6alk syulb,s -tSitu-Cte1d-6al wkyitlhf}

, ^{a f s}

n^{roa dmid A –N 1r1, R1 t9o Ar4 R23,} w_{herein each of said -C} ⁰

1_{-6alkyl is optionally} ^; h _{and independently substituted with from 1 to 3 - 35 Het1 h,a Hloe;t2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle}

H_{aevt4in,g H ferotm 1 to 3 heteroatoms selected from O, N and S; wherein each of said Het1, Het2, substituen5t,s H seetl6e,ct aendd fr Homet7– ihsal oop,t -ioOnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-Ctit1u-6teadlky wl,it =hO f,ro -(mC= 1O) t-oC13-} 6 _s ^a _u ^l _b ^k _s ^y _t ^l, _itu ^a _te ⁿ _d ^d _w -_i ^N _th ^R _f ² _r ¹ _o ^R _m ²² ₁ ^; _t ^w _o ^h ₃ ^er -^e _h ⁱ _a ⁿ _lo; ^{each of said -C1-6alkyl is optionally and ind}

^{p d tly -63- Het8 a is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N wnhder Se;in at least one of said heteroatoms is attached}

5 ^{w wh ein}

s^eher

l^{eercetein w}

d ^{s fah}

r^oiedn

m ^{H R}

–^e1

h^{ta8 is}

l ^ios–H

, ^{o -Op,t t}

H^{ihoe n o}

,ⁿⁿ

–^{a a}

C^llyt

1^{-6 a le}

a^na

l^kdst

y ^il,dn

-^{Ceep h}

1^{eentdeeronatltyom t}

s^{ub oo}

s^{f X}

t ^H1

i^{tue o}

t^te8r

d ^{i Xs2}

w ^a;

i^{ttthac fhroemd t 1o t Xo2; 3 a snudbstituents -O-C -6}

1^{-6alk alkylene, -C1-6alkyl-C3-6cycloalkyl, -C3-6cycloalkyl, each of sayidl, - -CS-1C1-6}

-^{6alkayllk iysl, o =pOtio, -}

^{(Clly=O)-dC i1-6dalkpyl,d -Cen1-t6laylk syulb-Ost-iCtu1t-e6alkyl and -NR21R22; wherein 10 Z1, Z2, Z3, Z4 and Z5 are each indep d tly l td from C and Nd with from 1 to 3 -halo;}

I^{n a st sepreeociisfiocm eemr,b toaduitmomenetr, t rhaece pmreics,e mntet ianbvoelnitteio,n pro p-ro ovrid peresdr a com.pound of formula Ia or a solvate thereof as defined in anyone of c ug, salt, hydrate, N-oxide form, or and Z and wherein the further deflianiimtiosns 1 a tond 6, p wrohveisreioinns ea acsh d oeffi snaeidd h Ze1,re Zin2}

5 ^{is C; , a Zb3,ov Z4 5 app e 1 ly.}

I^{n a} _st ^s

o_e ^p

l_vre ^e

a_o ^c

t_ei ⁱ _s ^fi

t_o ^c

h_m ^e

e_re ^m

e_ro, ^b

f _t ^o _a ^d

a_u ⁱ

s_t ^m _{o dm} ^en

e_fe ^t

i_nr, ^t

e _r ^h

d_a ^e _{c ine} ^p _m ^re

a_nic ^s

y_, ^e

o _m ^nt

n_eet ⁱ

o_a ⁿ

f_b ^v

c_o ^e

l_l ⁿ

a_it ^t

i_e ^io

m_, ⁿ

s _{pr 1o} ^p-^ro

t_{o o} ^v _r ^id

7 _p ^e

,_re ^s _dr ^a _ug ^c _, ^o _s ^m _al ^p _t, ^o _h ^u _y ⁿ _d ^d _ra ^o _te ^f _, ^f _N ^or-^m _ox ^u _id ^la _{e f} ^I _o ^a _rm ^or _{, o} ^a s _{r 10-membered heterocycle having from wherein said Het8 is a saturated 3- to 20 wherein the further definitions and provis 1io tnos 3 as he dteefrionaetdom hesre sienle acbtoevde fr aopmply O., N and S; and I snter aeo sispoemcieficr, t eamutboomdeimr,e rnatce thmeic p,r meseetanbto ilnitvee,n ptiroon- o prro pvrieddersug a, s caoltm,p hoyudnradte o,f N f-oorxmiduela f I or a 25 solva i}

R_{1 isnt}

s_de

e _{A th orm, or A1 a le2e}

c _ar

t_ereeof

d _e,

f_{ra w}

o_ch

m_here

– _inHdne

H_{, ap}

-_{nendently selected from C and N;}

R_{5 i iss s seelleecctteedd f frroomm––H hdal–oh aanlod;}

R_{2 -C1-6alkyl; 30 R3 is selected from–H and -C1-6alkyl;}

X _{X1 is selleecctteedd f frroomm– -OC-C a1n-l6d}

k_{a - yllkC}

-_y1

,_{l- –-6,a}

O _-l

-_Nky

C_{Rl;3-C1-6alkyl-, -NR3}

2 _{is se 1-6a 1-6alkyl-, -NR2-C1-6-a,l -kO-;}

H_{et8 isb ast 3it-u to 10-membered heterocycle; wherein said Hyel-t,8 - iNR2-, -O-;}

s_u ^k _e ^y _n ^l _t ^, _s - _{selected from–halo, -OH,–C1-6alkyl, -C1-6alksyle onpetio,n -Cal3l-y6c syucblosatiltkuytel,d -C w1i-t6hal 1ky tloC33-} ^{35 Z 6cycloal}

^{(C=O)-C1-6ahlk Cyl, and -(C=O)-C3-6}

1^{, Z2, Z3, Z4 and Z cycloalkyl ; and} M _{A1o arend pr Ae2fe arraebl eya,ch independently selected from C and N;} ^{-64- R R1}

5 ^{i iss s seelleecctteedd from–H and–halo;}

R^{2 is selected f frroomm––HH, a -nhdalo and -C1-6alkyl; 5 R3 is selected from–H and - -CC1-6}

1^-6aallkkyyl;

X _X ¹

2 ⁱ _i ^s _s ^s _s ^e _e ^l _l ^e _e ^c _c ^t _t ^e _e ^d _d ^f _f ^r _r ^o _o ^m _m ^– _– ^O _O--^C _C ^1-6

1_-6 ^a _a ^l _l ^k _k ^y _y ^l _l ^{-, -NRl;3-C1-6alkyl-, -NR3-, -O-;}

H_{et8 is a 3- to 10-me -, -NR2-C1-6alkyl-, -NR2-, -O-;}

s_{ubstituents selemctbeedre frdom het–ehroacloy,cl -eO;H w,he–rCe1in-6a slakiydl, H -eCt8}

1_{-6 iaslk oyplteionnea,ll -yC s3-u6cbysctiltouatelkdyl w} k^ylC3-6 _{,i athnd 1 t -oC13-} ^{10 Z 6}

1 ^al

E^{v,e Zn2, cycloalkyl; and}

m ^{Zo3r,e Z p4r aenfedra Zb5l ay,re A e1a isch N C a.nd A2 is C.}

I ^{snter aeo sipsoemcifeicr, e tamubtoomdiemr,en ratc tehmeic p,re mseetnatbo inlivtee,nt pioron- p orro pvirdes a compound of formula Ia or a 15 solvate thereof, wherein edrug, salt, hydrate, N-oxide form, or R} _R ¹

5 ⁱ _i ^s _s ^{selected from–H and–halo;} _{20 R2 is a settlaecchteedd f troom Z1– aHnd an is selected from–H and -C1-6alkyl;}

R _X3

1 _{i iss s seelleecctt d -C1-6alkyl;}

e_{edd f frroomm––OH- aCnd -C1-6alkyl;}

X _1-6

2 _{is sele alkyl-, -NR3-C1-6alkyl-, -NR3-, -O-;}

H_{et8 is acte 3d- fr toom 1–0O-m-Ce1m-6ablekryel-d, -N NR-c2o-Cnt1a-6inailnkgyl-, h -eNteRr2-, -O-;}

s_{ubstituted with 1 to 3 substituents selected fromo–chyaclloe,; -O wHhe,r–ein said Het8 is optionally} ²⁵ _{C1-6alkyl, -C1-6alkylene, -C3-} 6 ^{NcRycloalkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

^{(C=O)-C1-6alkyl, - Z21}

3^{R, Z2 C1-6alkyl-O-C1-6alkyl and - Z 2}

1^{, Z2, 4 ; a anndd Z5 are each C.} _{30 s Inte yet another particular emb}

s_{olvreaoteis tohmereero,f t,a suetolemcteerd, f rraocmemo}

t_hice,di

l_{i mm}

s_tee

c_tn

o_atb,

m_{o t}

p_lhirtiee

s_{, p present invention provides a compound or a ingr:o- or predrug, salt, hydrate, N-oxide form, or} ^-65- _C

_{p d N1 E pl N1 Cp d N2 E pl N2 C}

_{p d N3 E pl N3 Cp d N4 E pl N4 Cp d N5 E pl N5 Cp d N6 E pl N6 C}

_{p d N7 E pl N7 Cp d N8 E pl N8} ^-66- _C

_{p d N9 E pl N9 Cp d N10 E pl N10 C}

_{p d N11 E pl N11 Cp d N12 E pl N12 C}

_{p d N13 E pl N13 Cp d N14 E pl N14}

C_o

_{p d N15 E pl N15 Cp d N16 E pl N16} ^-67- _C

_{p d N17, E pl N17 Cp d N18, E pl N18 C}

_{p d N19 E pl N19 Cp d N20 E pl N20 C}

_{p d N21, E pl N21 Cp d N22, E pl N22 C}

_{p d N23 E pl N23 Cp d N24 E pl N24} ^-68- _Co

_{p d N25 E pl N25 Cp d N26 E pl N26 Cp d N27 E pl N27 Cp d N28 E pl N28 C p d N29 E pl N29 Cp d N30 E pl N30 Co}

_{p d N31 E pl N31 Cp d N32 E ple N32} ^-69- _Comp

_{d N33 E pl N33 Cp d N34 E pl N34 Co}

_{p d N35 E pl N35 Cp d N36 E pl N36 Co}

_{p d N37, E pl N37 Cp d N38, E pl N38 Co}

_{p d N39 E pl N39 Cp d N40 E pl N40} ^-70- _Co

_{p d N41, E pl N41 Cp d N42, E pl N42 Comp}

_{d N43 E pl N43 Cp d N44 E pl N44 Co}

_{p d N45 E pl N45 Cp d N46 E pl N46 C}

_{p d N47 E pl N47 Cp d N48 E pl N48} ^-71- _C

_{p d N49, E pl N49 Cp d N50, E pl N50 Cp d N51 E pl N51 Cp d N52 E pl N52 C}

_{p d N53 E pl N53 Cp d N54 E pl N54 C}

_{p d N55, E pl N55 Cp d N56, E pl N56} ^-72-

C

_{p d N57 E pl N57 Cp d N58 E pl N58}

_C

_{p d N59, E pl N59 Cp d N60, E pl N60}

_C

_{p d N61, E pl N61 Cp d N62, E pl N62}

I_{n a} ^{Cp d N63, E pl N}

c _{pormefperrirseindg e:mbodiment, the pre} ⁶ _se ³ _{nt invention provides a compound selected from the list} ^-73-

C_omp

_{d N27 E pl N27}

C^{p d N59 E pl N59} C_{op d N43 E pl N43}

C_{p d N60 E pl N60 Cop d N44 E pl N44 Cp d N62 E pl N62 Cop d N45 E pl N45}

^{Cdp d N63 E pl N63} _{Preferably the present invention provides a compound which is} ^-74-

a_nd ^Co

^{p d N60 E pl N60 Cp d N45, E pl N45. I} _h ⁿ _et ^p _e ^a _ro ^rt _a ^ic _ry ^u _l ^la _m ^r _o ⁱⁿ _iet ^t _y ^he _at ^c _p ^o _o ^m _si ^p _ti ^o _o ^u _n ⁿ _Z ^d ₁ ^s _in ^a _a ^cc _cc ^o

a_{. o} ^rd _rd ⁱⁿ _a ^g _nc ^to _{e w} ^th _it ^is _{h t} ⁱ _h ⁿ _e ^ve _n ⁿ _u ^ti _m ^on _b ^, _er ^t _i ^h _n ^e _{g a} ^R _s ⁵ _p ^is _ro ^l _v ⁱⁿ _id ^k _e ^e _d ^d _in ^to _F ^t _o ^h _r ^e _mu ^a _l ^r _a ^yl _{I o} ^o _r ^r _{5 I}

-75- F ^{sauirdth ceormmpooreu,n tdhe is p threes Sen-etn invention provides a compound according to this invention, wherein F sauirdth ceormmpooreu,n tdhe is p threesent inavnetinotmioenr. provides a compound according to this invention, wherein 5 T prhoevi cdoemdp inou thneds ex oaf the R p-erensaenntitom inveer.ntion can be prepared according to the reaction schemes only illustrative for tmhepl iensve hnetrioeinna afntedr, th bautt t thhose skilled in the art will appreciate that these are any of several standard synthetic processees co cmompomuonndlsy o ufs tehdis b inyve thnotisoen s ckainlle bde i prepared by 10 organic chemistry. n the art of I vnet ae preferred embodiment, the compounds of the present invention are useful in human or inhibrinary medicine, in particular for use as kinase inhibitors, more in particular for the The pitiroense of LRRK2 kinase.}

u^{se of a cnotm inpveonsittiioonn fu crotmheprri psrinogvid seasid th ceo umspeo ouf a compound as defined hereinbefore or the} _{15 p toar Ptiacruklianrs foonr’s th deis peraesveen atniodn A alnzhde/oimr terer’ast dmiseenat of n} ⁿ _e ^d _u ^, _ro ^a _l ^s _og ^a _ica ^h _l ^u _d ^m _is ^a _o ⁿ _rd ^o _e ^r _rs ^v _s ^e _u ^te _c ^r _h ⁱⁿ _a ^a _s ^ry _bu ^m _t ^e _n ^d _o ⁱ _t ^ci _l ⁿ _im ^e _i ^, _te ⁱⁿ _{d I hner aein pbreeffoerrere odr t ehmeb uosdeim oefn at, co thmepo insviteionntions pero.vides the use of a compound as defined treatment o comprising said compound in the prevention and/or 20 A f neurological disorders such as but not limited to Parkinson’}

T _cohlz

m_ehe

p _pi

r_rm

i_esse

i_ner’

g_{nst d}

s _inis

a_{ve s disease and ideans}

c_teioo.

m_{np fuoruthnedr p fororv uidsees a in co thmepo purnedve anstio dnefin aendd/ hoereinbefore or a composition disorders such as but not limited to Parkinson’s disease and Alzhreim treear’tsm deisneta osfe. neurological 25 F nuumrthbeerre edm sbtaotdeimmeennttss: of the present invention are detailed herein below in the form of 1 p.redrug, A sa clot,m hpyodurantde, o Nf- Fooxirdmeu floarm I o,r or a s sotlevareteoi tshoemreeor,f, tautomer, racemic, metabolite, pro- or}

³⁰ _Wherein

^I -76- R^{1 is( te}

w^{C s=eSle)c-R4d, f -rSoOm2-–RH4,,– -ChaNl,o, -N -ORH9-,S -OC1-6}

2^{-Ra4lk,y -lC,3 --O6c-yCc1l-o6aallkkyyll,, - -SO--CC1-6}

3^{-6aclykcyllo,a -NlkRyl9,R -1A0,r1 -( aCn=dO–)-HRe4,t1 -;} 5 _su ^h _b ^e _s ^r _t ^e _i ^{in each of said -C} _1-6 ^{alkyl is optionally and independently substituted with from 1 to 3} R_{5 is 6}a _alk_tty_al_ct

,_hu

-N_eednts

R_{6 to s}

R_{7 Ze}

,_1le

-( _{octed from–halo, -OR35, -NR11R12, -O-C1-6alkyl, and -S-C1-6alkyl;}

C_r= _ZO₅) _a-R_nd8, _i -_s(C _se=_lS_e)_c-_tR_e8d, _f -_rS_oO_m2-_–R_H8,,_– -C_hN_al,_o, -N _-OR_H6-_,S -O_C1-6

2-R_a8l,_ky -C_{l,3 --6O}c-y_Cc₁lo_-6a_al_lk_ky_yl_l,_, - -O_S--_CC_{1- 3-} 6 _s ^c _u ^y _b ^c _s ^lo _tit ^a _u ^lk _te ^y _d ^{l, -} _w ^A _i ^r _th ^{5 a} _f ⁿ _ro ^d _m ^–H ₁ ^et _t ⁵ _o ^{; w} ₃ ^h _s ^e _u ^re _b ⁱ _s ⁿ _tit ^e _u ^a _e ^c _n ^h _ts ^of _s ^s _e ^a _le ^id _ct -_e ^C _d ^1-6 _fr ^a _o ^lk _m ^yl _– ^is _ha ^o _l ^p _o ^t _, ^io -ⁿ _O ^a _R ^lly ₃₆ ^a _, ⁿ _-N ^d _R ⁱⁿ ₂ ^d _3R ^ep ₂₄ ^e _, ⁿ -^d _O ^e-ⁿ _C ^tl ₁ ^y-_{10 R} ⁶

2 _is ^a

6^a _s ^lk

l^k _e ^y

y_le ^l,

l_c ^a

i^s _te ⁿ

o_d ^{d - p} _f ^t _r ^S

i_o- ^o _m ^C1

n^al _– ^-6alkyl;

l^y _H, ^a _{-halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-} f^{rom–halo,–OR} ₂₇ ^{, anndd - inNdRe} ₁ ^p ₃ ^eRn ₁₄ ^{dently substituted with from 1 to 3 substituents selected} R_{3 is} ⁶ _{selected from–H, -halo, -OH,} ^; _{-C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1- 15 R a fnr} ^a _o ^lk

d_m ^yl

R_– ⁱ

8_h ^s

a_a ^{o ionally and i}

r_leo ^p _, ^t

e_– ^{ndependently substituted with from 1 to 3 substituents selected} a_{OcRh2 i8n,d aenpde -nNdRen15tRly16}

4 _{s;elected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R^{, R 6a7l,k Ryl9, -NR17R18, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar4 and -Het4}

6 ^{; 20 R , R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31}

3^{4, R35 and R3 , R32, R33, C 6}

o^{p1-t6ioanlkaylll,y - aSn-Cd1- i6na a}

d^lr

e^{keypl each independently selected from–H, -halo, =O, -OH, -C1-6alkyl, -O- e,n -dCe3n-6cycloalkyl, -Ar6 and–Het6; wherein each of said -C1-6alkyl is} h_{alo,–OH, -O-C1-6alkyl, -S-} ^t _C ^ly _1-6 ^s _a ^u _lk ^b _y ^s _l ^{tituted with from 1 to 3 substituents selected from–} R _{and R28 are each independently sele,c -tCe3d-6 fcryocmlo–aHlk,y -l, -Het6, -Ar6 and–NR37R38}

2_{7 ;}

R_{7 and R38 are each independently selected from–H,C -h1a-6laol,k -yl, -C3-6cycloalkyl and -Het2 3 : 25 X C1-6alkyl, -Cr3o-6 OH, -C1-6alkyl, -O-C1-6alkyl, -S- 1 is selected f mcy–cClo1a-6lkaylkl,y -l-A,r–7O an-Cd1–-6Halekty7l;-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,u -tNedR w3-i,th and -O-; wherein each of said -C1-6alkyl- is optionally and independently} -_{S-C1-6alkyl, -phe} ^fr _n ^o _y ^{m 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl,} _{30 X2 is} ^6a _s ^lk _e ^y _le ^l- _c ^, _te ^-N _d ^R _fr ² _o ^-, _m ^a _– ⁿ _C ^d _1l

-_-,6 ^O _{a a}

-_ln

;_kdy ^w _{l --N}

h_, ^e _–R

r_O33

eⁱ _-R

n_C34

1 ^e _-;6 ^a _a ^c _l ^h _ky ^o _l- ^f _, ^s _– ^a _S ⁱ-^d _C -₁ ^C _-6a ^1- _l ⁶ _k ^a _y ^lk _l- ^y _, ^l --_C ^is _1-6 ^o _a ^p _lk ^t _y ^io _l- ⁿ _N ^a _R ^lly _2-C ^an _{1-6alkyl-, -NR2-C1-} s^{ubstituted with from 1 to 3 substituents selected from–halo, -OH, -C1-6aldky iln,d -Oependently -S-C1-6alkyl, -phenyl and -NR31R32 -C1-6alkyl,} ₃₅ ^Ar1, _o ^{Ar4, Ar5, Ar6, and Ar7 are each; independently}

A_{pr5t,ion Aarl6l,y c aonmdp Arirs7ing be 1in tgo 3 op hteiotenraolalytom ansd se inledcetpeed} ^a

n _fdro ⁵

e_m- n_{tl O} ^to

y_{, s N} ¹⁰

u_{b a}- s_n ^m

t_d ^em

i_{tu Ste;} ^{bered aromatic cycle} d _{ea wchith of f sroamid A 1r1, Ar4, substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19 toR203 wherein each of said -C1-6alkyl is optionally an ; -halo; d independently substituted with from 1 to 3} -77- H^{et1 h,e Hteerot2c,y Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered said Het1c,le He hta2,vi Hnegt4 f,ro Hm 1 to 3 heteroatoms selected from O, N and S; wherein each of 5 from 1 to 3 substituentest5 s,e Het6, and Het7 is optionally and independently substituted with = inOde,p -}

^{(C=dO)t-lCy1-6ablkytilt,t aendd w -lNected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, ithR fr2o1Rm221; t woh 3e -rein each of said -C1-6alkyl is optionally and Het8 is a 3- t 10- b ed heterocycle havinhga flro;}

a^{nd om 1 to 3 heteroatoms selected from O, N wher S;}

1^{0 s Cu3b-6scte}

y^iti

c^un

l^{oean s}

l^ta

k^{sid sel Hecette8d i fsrom op–tihoanlaol,ly -O aHn,d–C in1-d6aelpkeynl,d -eCn1t-6lyalk syulebnseti,tu -tCe1d-6a wlkiythl-C f3r-o6cmyclo 1al tkoyl, 3 - NR yl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

^(C=O)-C1-6

2^{1R alkyl, -C1-6alkyl-O-C1-6alkyl and -} f_rom ^{22; wherein each of said -C1-6alkyl is opti lly d idpendently substituted with} w _{1 to 3 -halo;}

1_{5 Z herein when R1–H, then at least one heteroatom of Het8 is attached to X2}

A₁

1_{, a Zn2d, Z A3}

2_{, a Zr4e a enadc Zh5 in adreep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and 2}

2_{0 R.1 is sel Aec cteodmp frooumnd–H as,– dheafilnoe,d -O inH s,t -aCte1-m6aelknytl 1, wherein}

( _{wCh=eSre)-inR4 e,a -cShO o2f-R sa4,id -C -CN, -NR9-SO2-R4, -C,3 --O6-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - 1-6alkyl is optio cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; s su abttsatcithueednts to s Ze1le ocrte Zd5 f aronmd i–sh saelole,c -tOeRd3n}

f_5r,a

o _{-lly and independently substituted with from 1 to 3 R mNR–1H1R,–12h,a -O-C1-6alkyl, and -S-C1-6}

5 _{i alkyl;}

C_{1-6alkyl, -S-C1-6alkyl, -NR6R7, -(C=O)-R8, -(C=Slo, -OH, -C1-6alkyl, -OH, -C1-6alkyl, -O-} ²⁵ _{)-R8, -SO2-R8, -CN, -NR6-SO2-R8, -C3-} 6 ^{acnydcl ionadlekpyle,n -dOe-nCt3ly-6c syucblosatitlkuytel,d -A wri5th an frdom–H 1e tto5; 3 w shuebresitni each of said -C1-6alkyl is optionally} N_{R23R24, -} ^{tuents selected from–halo, -OR36, -} R _{is selectedO fr-oCm1-6–aHlk,yl -,h aanlod, - -SO-CH1,-6}

2 _{-aClk1-y6la;lkyl, and -C3-6cycloalkyl; wherein each of said -C1- 30} ^{6alkyl is optio}

R_{3 is fro smele–chtealdo, fr–oO} ⁿ

m_R ^al

–₂ ^ly _7H, ^a

, _a ⁿ _n ^{d independently substituted with from 1 to 3 substituents selected} -_{hda -loN,R -1O3RH1,4; -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-} 6 _f ^{alkyl is optionally and independently substituted with from 1 to 3 substituent 35} _{nrodm R–8h aarleo, e–} ^{s selected} R _{aOcRh2 i8n,d aenpde -nNdRen15tRly16}

4 _{a s;elected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} R ⁶

6^{, Ra}

R^{7l,k Ryl9,, -N RR17}

1^{0, RR18}

1^{1,, R -C3-6}

1^{2,c Ry1c3l,o Ra1lk4,yl R, -1O5,- RC3-6}

1^{6,c Ryc17lo,a Rlk18y,l, R -A19r,4 R a2n0d, R -H21e,t R4;22, R23, R24, R31, R32, R33} C³⁴

1_-6 ^, _a ^R _lk ³ _y ⁵ _l, ^an _-S ^d- ^R _C ³⁶

1_-6a ^a _l ^r _k ^e _yl ^e _, ^a -^c _C ^h _3- ⁱ ₆ ⁿ _c ^d _y ^e _c ^p _lo ^e _a ⁿ _lk ^d _y ^e _l ⁿ _, ^t -^ly _Ar ^s ₆ ^e _a ^le _n ^c _d ^te _– ^d _H ^f _e ^ro _t6 ^m _{; w} ^–H _he ^, _r -_e ^h _i ^a _n ^lo _e ^, _a ⁼ _c ^O _h ^, _o ^-O _{f s} ^H _a ^, _i ^{-C1-6alkyl, -O-} o_{hpatloio,n–aOllyH, a -nOd-C in1d-6eaplkeynl,d -eSn-tCly1-6 saulkbyslt,it -uCte3-d6c wycitlhoa flrkoyml, - 1He tot6, 3 -A sru6b asntditu–eNnRts37 sRed}

3_{l8e;c -Cte1d-6a frlkoyml i–s 40} -78- R ^R27

7 ^{a anndd R R28}

3^{8,, a arree e eaacchh i innddeeppeennddeennttllyy s seelleecctteedd f frroomm––HH,, - -Ch1a-6loa,lk -yOl,H -,C -3C-6}

1^{c-y6acllkoyall,k -yOl a-Cnd -Het2 3 :} C _{yl, -C} ^1-6

1_{-6alk 3-6cycloalkyl,} ^{alkyl, -S- 5} _{X1 is selected from–C1-6alky -l-A,r–7O an-Cd1–-6Halekty7l;-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1- X} ⁶

2 _is ^a _s ^lk _e ^y _le ^{l- al} _c ^, _t -_e ^N _d ^R _f ³ _r-_om ^and _–C ^– ₁ ^O _-6-_a ^; _{lkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} A^{r 6}

1^,

1^{0 o Aprk}

t^4y

i^{o,l- n A,}

a^{r - ll5N}

y^,R

c ^A2

o^{r- m6,, an}

p ^ad

r^{insd -O}

i^{ng A-;}

1^{r7 to ar 3e h eeatecrhoa intodmepse snedleecnttelyd a 5- to 10-membered aromatic cycle A sur5b,st Aitur6e,n atsn sdel Aecr7ted be frinogm o–phtaiolon,a -lOlyH a,n -Cd1-6 inadlkeypl,e -n f}

O^dro

-^em

C^{n1t-l O}

6^y,

a^{lk s Nub asntditu Ste;d ea wchith of f sroaimd A 1r1, to Ar43, wherein each of said -C1-6alkyl is optionally and indepen yl, -S-C1-6alkyl, and–NR19R20;}

^{15 1 - h,ha n y}

s^{ae Hl dently substituted with from 1 to 3 Het o itdee;}

r ^Hot2c,

e^{yt1c H}

,^leet4

H^{e h,}

t^{a2,v Hi Hne}

e^gt5,

t^{4 f,ro H}

H^met6

e^t51,

, ^{t Ho an}

e ^3d

t^{6, h ae H}

n^teet

d^{r7o Ha a}

e^ttore

7^{m iss ea}

o ^sc

p^eh

t^{iloenc itaed}

l^ldep

y ^{f are}

n^on

d^mde

i^{n On}

d^,tl

e ^{Npe a a 3- to 10-membered nnd S; wherein each of from 1 to 3 substituents selected from–halo, -OH,–C1-6alkyl, -O-dCently substituted with =O, -}

^{(C=O)-C kyl, and -NR 1-6}

1^{-6al 21R22; wherein each of said -C1-6a alkyl, -S-C1-6alkyl, 20 indep d tly btitted with lkyl is optionally and Het8 a insd a 3- t 10- b ed hetero frcoymcle 1 h toav 3in -hga flroo;m 1 to 3 heteroatoms selected from O, N} w _suhbesr ^S

t_e ^;

i_{tiunen stasid sel Hecette8d i fsrom op–tihoanlaol,ly -O aHn,d–C in1-d6ependently substituted with from 1 to 3 25 C3-6cycloalkyl, -O-C1-6alkyl, -S alkyl, -C1-6alkylene, -C1-6alkyl-C3-6cycloalkyl, - N froRm21R 122; wherein each of said-C -C1-6}

1_{a-6laklykly,l = iOs, o -p}

_{(tCi=Ol)l-yC1-6adlk iydl, -pCe1n-6daelknytll-yO s-uCb1s-6taitluktyeld an wdith - wherein to w 3h -ehnalo;}

Z _{R1 is–H, then at least one heteroatom of Het8 is attached to X2}

A₁

1_{, a Zn2d, Z A3}

2_{, a Z4 and Z5 are each independently selected from C and N; and}

3_{0 re each independently selected from C and N.}

3 _{R.1 is s=eSl Ae)c c}

-_tReo

4_dmp

, _{f -ro}

S_ou

O_mnd

2_{-–RH as}

4_{,,– d}

-_Cheafi

N_ln

,_oe,d

-_{N -O in}

R_{H s}

9_-,t

S _-a

O_Cte1-m6

2_{-aelknytl, 1, -O w-hCe1r-e6ain}

(_{C lkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - wherein each of said -C1-6alkyl i R4, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar1 andm– 1H teot13; 35 in}

R_{5 is su abttsatcithueednts to s Ze1le ocrte Zd5 f aronmd– ish saelos}

l_{e, o}

c _-Opt

t_eRio

d_3n

f_5r,a

o _-ll

m_{NyR a}

–_1n

H_1dR,1–2h,d

a _-eOp

l_o-e

,_Cn

-_O1d-6e

H_an

,_lktl

-_yy

C_{l, s}

1 _au

-_6nb

a_dst

l_{ky -itSu}

l_,-t

-_Ced

O_{1--6 with fro}

C_{a1lk-6yall;kyl, -S-C1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- 6 _s ^c _u ^y

l_b ^c

k_s ^lo

y_tl,_it ^a _u ^lk

a_tn_e ^y

d_d ^{l, -} -S _w ^A

-_i ^r

C_th ^{5 a}

1_{-6 f} ⁿ _ra_o ^d

lk_m ^–H

yl; ₁ ^et _t ⁵ _o ^{; w} ₃ ^h _s ^e _u ^re _b ⁱ _s ⁿ _tit ^e _u ^a _e ^c _n ^h _ts ^of _s ^s _e ^a _le ^id _ct -_e ^C _d ^1-6 _fr ^a _o ^lk _m ^yl _– ^is _ha ^o _l ^p _o ^t _, ^io -ⁿ _O ^a _R ^lly ₃₆ ^a _, ⁿ _-N ^d _R ⁱⁿ ₂ ^d _3R ^ep ₂₄ ^e _, ⁿ -^d _O ^e-ⁿ _C ^tl ₁ ^y 40 - ₆a -79- R₂ is selected from–H, -halo, -OH, -C_1-6alkyl, and -C_3-6cycloalkyl; wherein each of said -C_1- 6 _fr ^a _o ^lk _m ^yl _– ^{is optionally and independently substituted with from 1 to 3 substituents selected 5} _{R is selechtealdo, fr–oOmR–27H,, an -hda -loN,R -1O3RH1,4}

3 _{; -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-} 6 _fr ^a _o ^lk _m ^yl _– ⁱ _h ^s _a ^o _lo ^p _, ^ti _– ^o _O ⁿ _R ^al ₂ ^ly _8, ^a _a ⁿ _n ^d _{d -} ⁱⁿ _N ^d _R ^e ₁ ^p ₅ ^e _R ⁿ ₁ ^{dently substituted with from 1 to 3 substituents selected} R _{nd R re each independently6}

4 _{a 8 a s;elected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} ^{10 R 6}

6^{, Ralk Ryl, -NR17R18, -O-C3-6cycloalkyl, -C3-6cyclo}

R^{7, R -H ; C1-6 R9}

a^l3,

k^{5 R}

y ^a1

l^,n0

-^{d, R}

S^{- R11}

C^36,

1^{-6 a R}

a^r1

l^e2,

k^{y e R}

l^,a1

-^c3

C^{h, R}

3 ^i-n1

6^cd4

y^e,

c^{p R}

l^oe1

a^n5,

l^{d R}

k^{eyln16 1}

,^{t,l -y R}

A ^sr6e7,

a^{le Ral nc1k dte8y,l, –d R - H f1A}

r⁹

e^{o,r4 tm R a2n 6; w–0H,d he,r -2}

e^{h1e,t ia R4 nlo2}

e^,2

a ^=,

c^{O R2}

h^,3

o ^{-,O R4}

f ^sH2

a^,,

i^{d -C R31}

-^1C-6,

1^{a R32, R33 34 ,}

-^{lkyl, -O- optionally and independently substit 6alkyl is} h ^{uted with from 1 to 3 substituents selected from–} _{15 R27 anadlo R,–28O,H a, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38;}

R _{a Cn1d-6a Rlk38y,l, ar}

-_re

C_{e e}

3 _{eaacchh i innddeeppeennddeennttllyy s seelleecctteedd f frroomm––HH,, - -Ch1a-6loa,lk -yOl,H -,C -3C-6}

1_{c-y6acllkoyall,k -yOl a-Cn1d-6 -aHlkeytl2 37 ,: -S- X -6}

1 _{is selected fromcy–cClo1a-6lkaylkl,y -l-A,r–7O an-Cd1–-6Halekty7l;-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,u -tNedR w3-i,th an frdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe slaeicdte -dC f1r-o6amlky–l-ha islo o,p -OtioHnally and independently} _{20 X -S-C1-6alkyl, -phenyl, and -NR33R34} ^{, -C1-6alkyl, -O-C1-6alkyl,} 2 _{is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2} 6^a _-C1- s^{ulbksytl-it,u -tNedR w2-,ith an frdom -O 1-; to w 3herein each of said -C1-6alkyl- is optionally and independently -S-C1-6alkyl, -phenyl and -N substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, 25 Ar, o Aprt4, Ar5, Ar6, and Ar7 areR3 e1Rac32}

1 ^{h; independently a 5- to 10-membered aromatic cycle Ar5,ion Aarl6l,y c aonmdp Arisring 1 to 3 heteroatoms selected from O, N and S; each of said Ar1, Ar4, substituents selec7ted be frinogm o–phtaiolnally and independently substituted with from 1 to 3 wherein each of said -C1-6alkyl io, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19R20; 30 s optionally and independently substituted wit}

H_et1 ^{-halo; h from 1 to 3} h_{,e Hteerot2c,yc Hleet4 h,av Hinegt5, fro Hmet61, to an 3d he Hteetr7oa atorems ea scehle independently a 3- to 10-membered said Het1, Het2, Het4, Het5, Het6, and Het7 is optionctaelldy f arnodm in Od, N and S; wherein each of from 1 to 3 substituents selected from–halo, -OH,–C1-6alkyel,p -eOn-dCe1ntly substituted with 35 = inOde,p -}

_{(C=dO)t-lCy btitt aendd w -iNthR -6}

1_{-6alkyl, fr2o1Rm221; t woherein each of said -C1-6alkyla islky ol,pt -iSo-nCa1ll-y6al aknydl, Het8r iosm a O b,i Nl t 3- t 10-membered hetero 3c -yhcalelo;}

f _{having from 1 to 3 heteroatoms selected 40 w whheerreeiinn a wt a}

h _leen

n_{ads S}

R_t;

1 _{o inse– oHf, s tahiedn h aette leroaastto omnes i hse atettraocahtoemd t oof X H1e ot8r i Xs2 a;ttached to X2; and} -80- w ^{suhbesrteitiunen stasid sel Hecette8d i fsrom op–tihoanlaol,ly -O aHn,d–C in1-d6aelpkeynl,d -eCn1t-6lyal substituted with from 1 to 3 C3-6cycloalkyl, -O-C1-6alkyl kylene, -C1-6alkyl-C3-6cycloalkyl, - NR , -S-C1-6alkyl, =O, -}

^{(C=O)-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and - 5 21R22; wherein each of said -C1-6alkyl is opti lly d idpendently substit}

Z _A1

1_{, a Z} ^fr

n₂ ^o

d_, ^m _Z ^{1 to 3 -halo; uted with} A₃

2_{, a Zr4e a enadc Zh5 in adreep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and}

_{10 4 p.redrug, A sa clot,m hpyodurantde, o Nf- Fooxrimdeul faor Ima, o orr a so sltvearteeo tishoemreeorf,, tautomer, racemic, metabolite, pro- or}

W^h

^I

R^{1 iesre te}

1₅ ^{(C s=ein}

S^{le)c-R4d, f -rSoOm2-–RH4,,– -ChaNl,, -N -ORH9-,S -OC- 2-R4lk,y -lC, -O-C- lkyl, -S-C- lkyl, -NR9R10, -(C=O)-R4, -} w _{suhbesrteitiune enatsch se olfe scateid} ^{3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1;}

d _{- fCro1m-6a–lkhyall ios, o -OptRio3n5,a -llNyR a1n1dR i1n2,d -eOp-eCn1d-6eanlktlyyl, s aunbstituted with from 1 to 3 R5 is attached to Z1 or Z5 and is selec}-_tR_e8d, _f -_rS_oO_m2-_–R_H8,,_– -C_hN_al,_o, -N _-OR_H6-_,S -O_C1-6

2-R_ad

8_l,_{ky -S}

-C_{l,- 3 -C}

-_{6O1--6Ca1lk-6yall;kyl, -S-C1- 6}

6a^cylk^cy^lol,^a -^lNR₆R₇, -(C=O)-R₈, -(C=S) cycloalkyl, -O-C_{3- 20 s} ^{kyl, -Ar5 and–Het5; wherein each of said -C1-6alkyl is optionally and inde}

6^a _u ^l _b ^k _s ^y _t ^l, _{ituted with from 1 to 3 substituents selected from–halo, -OR36, -NR23R} ^p ₂₄ ^e _, ⁿ -^d _O ^e-ⁿ _C ^tl ₁ ^y- _{R2 is selec} ^a _te ⁿ _d ^{d -} _fr ^S _o-_m ^C1 _– ^-6 _H ^al _, ^ky

6 _-h ^l; _{alo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1- 25 fr} ^a _o ^lk _m ^yl _– ⁱ _h ^s _a ^o _lo ^p _, ^ti _– ^{onally and independently substituted with from 1 to 3 substituents selected} R _is ⁶ _{selected froOmR–27H,, an -hda -loN,R -1O3RH1,4}

3 _{; -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1- fr} ^a _o ^lk _m ^yl _– ⁱ _h ^s _a ^o _l ^{ptionally and independently substituted with from 1 to 3 substituents selected} R _{nd R o,–aOcRh2 i8n,d aenpde -nNdRen15}

4 _{a 8 are e tRly16 s;elected from–hal} ^A _o ^r _, ⁴ _– ^a _{OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} ^{30 R 6}

6^{, Ralkyl, -NR17R18, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -} R⁷

C₃ ^{, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R2n0d, R -H21e,t R4;22, R23, R24, R31, R32, R33} 4_{, R35, an -Sd- RC36}

1_{-6a alrkeyl e,a -cCh3- i6ncdyecploeanlkdyeln,t -lyAr s6e alencdte–dH ferot6m; w–Hhe,r -ehianlo e,a =cOh, o -Of sHa,id -C -1C-6}

1_{-6alkyl 1a-6lkaylkl,y -lO is-} -81- o^{hpationally and independently substituted with from 1 to 3 substituents selected from– R27 andlo R,–28O,H, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38;} 5 _{R37 and R38,} ^{are each independently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2:} X _{C are each independently selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6}

1_{-6alkytel, alkyl, -S-} N_{d -C fr3o-6mcy–cClo1a-6lkaylkl,y -l-A,r–7}

1 _{is selec O an-Cd1–-6Halekty7l;-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,u -tedR w3-i,th an frdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe slaeicdte -dC1-6alkyl- is optionally and independently} _{10 -S} ^{from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl,} X_{2 is s-eCle1-c6atelkdyl f,ro -pmhe–nCy1l-,6a alnkdyl --N,–RO33-RC34}

1_{-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2-C1-} 6 ^{saulbkyl-, -NR2-, and -O-; wherein each of said -C1-6alkyl- is optionally and independently -Sstitutlekd with from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, 15 Ar1, o A-rC1-6}

4^{, Aar5,y Al,r -6p,h aenndyl A anr 2}

7^{d - aNreR3 e1Rac3h; independently a 5- to 10-m}

A^{pr5t,ion Aarl6l,y c aonmdp Arirs7ing be 1in tgo 3 op hteiotenraolalytom ansd se inledcetpeedn fdroemntl Oy, s Nub a m}

s^ntde

i^{tu Ste;b}

d ^eeare

w^{cdhith o afromatic cycle f sroamid A 1r1, t Ar4, substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19o 3 wherein each of said -C1-6alkyl is optionally and independently substituted with from 1R to20; 20 1 - h,ha}

e ^{Hl 3 Het o}

t^{e;t2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered saider Hoceyt1c,le He hta2,vi Hng from 1 to 3 heteroatoms selected from O, N and S; wherein each of from 1 to 3 substeittu4, Het5, Het6, and Het7 is optionally and independently substituted with =O, -}

^{(C=O)-C1-6alkyents selected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl,} 25 _Het8 in _isde _ap _3-d _{t 1}t₀ly- b_bti^lt^,

et ^aeⁿ

dd^d

h w ^-N

ei_tt_eh^R

r_o fr²

co^1R

ym^{22; wherein each of said -C1-6alkyl is optionally and} c_le 1 _h to 3 -halo;

a_{n aving from 1 to 3 heteroatoms selected from O, N w}

3_{0 suhd}

b_{esr S}

t_e;

i_{tiunen staid sel Hecette8d i fsrom op–tihoanlaol,ly -O aHn,d–C in1-d6aelpkeynl,d -eCn1t-6lyalk syulebnseti,tu -tCe1d-6a wlkiythl-C f3r-o6m 1l tkoyl, 3 C3 s - NR-6}

2_{c1yRc cycloa 2l2o;a wlkhyel,re -Oin-C ea1-c6ahlk oyfl, sa -Sid-C -C1-6}

1_{a-6laklykly,l = iOs, -}

_{(C=O)-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and - from 1 to opti lly d idpendently substituted with}

_{35 Z wherein w 3 - ahneh}

d_na

Z _Rlo1;

5 _{ar ise– eHac,h th iennde apte lenadsetn otlnye s heeletectreodat foromm o Cf H aentd8 i Ns. attached to X2}

1_{, Z2, Z3, Z4}

5 _{R.1 is A compound as defined in statement 4, whe}

(_{C s=eSle)c-tRe4d, f -rSoOm2-–RH4,,– -ChaNl,o, -N -ORH9-,S -OC1-6}

2_{-Ra4lk,y -lC,3 --O6c-yCc1r}

l_-e

o_6ain

a_{llkkyyll,, - -SO--CC1-6}

3_{-6aclykcyllo,a -NlkRyl9,R -1A0,r1 -( aC=O)-R4, - w suhbesrteitiune enatsch se olfe scateidd - fCro1m-6a–lkhyall ios, o -OptRio3n5,a -llNyR a1n1dR i1n2,d -eOp-eCn1d-6eanlktlyyl, s aunbdst -itSu-tCed1-6 wailtkhyl f;rnodm– 1H teot13; 40} -82- R₅ is attached to Z₁ or Z₅ and is selected from–H,–halo, -OH, -C_1-6alkyl, -O-C_1-6alkyl, -S-C_{1- 6}alkyl, -NR₆R₇, -(C=O)-R₈, -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_3- 6 _s ^c _u ^y _b ^c _s ^lo _tit ^a _u ^lk _te ^y _d ^{l, -} _w ^A _i ^r _th ^{5 a} _f ⁿ _ro ^d _m ^–H ₁ ^et _t ⁵ _o ^{; w} ₃ ^h _s ^e _u ^re _b ⁱ _s ⁿ _tit ^e _u ^a _e ^c _n ^h _ts ^of _s ^s _e ^a _le ^id _ct -_e ^C _d ^1-6 _fr ^a _o ^lk _m ^yl _– ^is _ha ^o _l ^p _o ^t _, ^io -ⁿ _O ^a _R ^lly ₃₆ ^a _, ⁿ _-N ^d _R ⁱⁿ ₂ ^d _3R ^ep ₂₄ ^e _, ⁿ -^d _O ^e-^{ntly 5} _{C1- R is} ^6a _s ^lk _e ^y _le ^l, _c ^a _te ⁿ _d ^d _f -_r ^S _o-_m ^C1 _– ^-6

2 _H ^al _, ^k -^y _h ^l; _{alo, -OH, -C1-6alkyl, and -C3-6cycloalkyl,; wherein each of said -C1-} 6 ^{fraolkmyl– ihsa olop,ti–onally and independently substituted with from 1 to 3 substituents selected} ₁₀ ^{R s selected fromOR–2H7,, a -hnadl -NR13R14}

3 ^{i ;}

o _{hpatloio,n–aOllyR2 a8,n adn idnd -Nep} ^{o, -OH, -C1-6alkyl, -C3-6cycloalkyl; wherein each of said -C1-6alkyl is}

R_{e1n5dently substituted with from 1 to 3 substituents selected from– R4 and R8 are each indepeRn1d6;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-} ^{15 R, R 6a7l,k Ryl9,, -N RR17}

1^{0R18, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar4 and -Het4}

6 ^{, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R;}

R ^{22, R23, R24, R31}

C³⁴

1^{-6,a Rlk3y5l, an -d R36 are each independently selected from–H, -halo, =O, -OH, -C1-6,a Rlk3y2l,, R -O33-, optionall S-C1-6alkyl, -C3-6cycloalkyl, -Ar6 and–Het6; wherein each of said -C1-6alkyl is} h_alo,–O ^y _H, ^a -ⁿ _O ^d _-C ⁱⁿ ₁ ^{dependently substituted with from 1 to 3 substituents selected from–} R _-6

2_{7 and R28, are each ianldkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38;}

2_{0 R a Cnd R ndeeppeennddeennttllyy s seelleecctteedd f frroomm––HH,, - -Ch1a-6loa,lk -yOl,H -,C -3C-6}

1_{c-y6cloalkyl and -Het2 37 38}

1_{-6alky,l, a -rCe3 each i alkyl, -O-C1-6alkyl,: -S- X s selected fro-6mcy–cClo1a-6lkaylkl,y -l-A,r–7O an-Cd1–-6Halekty7}

1 _{i l;-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1- X} ⁶

2 _is ^a _s ^lk _e ^y _le ^l- _c ^, _t -_e ^N _d ^R _f ³ _r-_om ^and _–C ^– ₁ ^O _-6-_a ^;

2⁵ _{lkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} A^{r 6}

1^,a

o ^Al

p^rk

t^4y

i^{o,l- n A,}

a^{r - ll5N}

y^,R

c ^A2

o^{r- m6,, an}

p ^ad

r^{insd -O}

i^{ng A-;}

1^{r7 to ar 3e h eeatecrhoa intodmependently a 5- to 10-membered aromatic cycle A s selected from O, N and S; each of said Ar1, Ar4, sur5b,st Aitur6e,n atsnd Ar7 being optionally and independently substituted with from 1 to 3 30 wherein each s oefle scatiedd -C fr1o-6malk–ylh iaslo o,pt -iOonHa,lly -C a1n-6dal iknydle,p -eOn-dCe1n-6talylk syul,bs -Stit-uCte1-d6a wlkiythl, fr–oNmR 119R to203;} H_et1 ^-halo;

h_{,e Hteerot2c,yc Hleet4 h,av Het5, Het6, and Het7 are each independently a 3- to 10-membered said Het1, Het2,i Hnegt4 f,ro Hmet51, to 3 heteroatoms selected from O, N and S; wherein each of 35 f =rOom, - 1(C t=oO 3)-C su1-b6satliktuyle,n atsn se Hleect6t,e adn fdro Hmet–7h isal oop,t -ioOnHa,lly–C an1-d6a ilnkdyel,p -eOn-dCe1n-6talylk syul,bs -Stit-uCt1e-6da wlkiythl, indep d tly btittedd w -iNthR fr2o1Rm221; t woherein each of said -C1-6alkyl is optionally and Het}

8 _{insd a S 3;- t 10- b ed heterocycle hav 3in -hga flroo;}

a _{m 1 to 3 heteroatoms selected from O, N} -83- w ^{suhbesrteitiunen stasid Het8 is optionally and independently substituted with from 1 to 3 C3-6cyclo selected from–halo, -OH,–C1-6alkyl, -C1-6alkylene, -C1-6alkyl-C3-6cycloalkyl, - NR21 alkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

^{(C=O)-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and - 5 f R22; wherein each of said -C1-6alkyl is opti lly d idpendently substitute}

w^{rom 1 to 3 -halo; d with Z1, Z2,h Zer3e,i Zn4 w ahnedn Z R1}

5 ^{ar ise– eHac,h th iennde apte lenadsetn otlnye s heeletectreodat foromm o Cf H aentd8 i Ns. attached to X2} _{10 6 R.1 is (C s=eSl Ae)c c}

-_{teodmp frooumnd–H as,– dheafilnoe,d -O inH s,t -aCte1-m6aelknytl, 4 - wOh-Cer1e-6ianlkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - whereinR4 e,a -SO2-R4, -CN, -NR9-SO2-R4, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; substituentsch s of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 R5 is attached to Ze1le ocrte Zd5 f aronm–halo, -OR35, -NR11R12, -O-C1-6alkyl, and -S-C1-6alkyl;}

15 _{d is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- 6}

6a^cylk^cy^lol,^a -^lN^kyR^l, ₆R ^-A ₇ ^r,⁵ - ^a(Cⁿ=^dO^–)^H-R^et ₈

5,^; -(C=S)-R₈, -SO₂-R₈, -CN, -NR₆-SO₂-R₈, -C_3-6cycloalkyl, -O-C_{3- substituted with from 1 to} ^w ₃ ^h _s ^e _u ^re _b ⁱ _s ⁿ _tit ^e _u ^a _e ^c _n ^h _ts ^of _s ^s _e ^a _le ^id _ct -_e ^C _d ^1-6 _fr ^a _o ^lk _m ^yl _– ^is _ha ^o _l ^p _o ^t _, ^io -ⁿ _O ^a _R ^lly ₃₆ ^a _, ⁿ _-N ^d _R ⁱⁿ ₂ ^d _3R ^ep ₂₄ ^e _, ⁿ -^d _O ^e-ⁿ _C ^tl ₁ ^y- _{R is} ^6a _s ^lk _e ^y _le ^l, _c ^a _te ⁿ _d ^{d -} _f ^S-C1-6

2 ^alkyl;

2^{0 6} _r ⁱ _o ^o _{m–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1- is fr} ^a _o ^lk

s_m ^yl

e_le– ⁱ

c_h ^s

t_ea ^o _ldo ^p _, ^t

f_r–oO ⁿ

m_R ^al

–₂ ^ly _7H, ^a

, _a ⁿ _n ^d

-_{hda -} ^{independently substituted with from 1 to 3 substituents selected} R _{loN,R -1O3RH1,4}

3 _{; -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-} 6^{alkyl is optionally and independently substituted with from 1 to 3 substituents selected} _{25 R ind,e R} ^fro

p_7e, ^m

n _R ^–

d_e9, ^h

n _R ^al

t_ly1 ^o ₀ ^, _, ^–

s _R ^O

e_l1e1 ^R

c_, ²

t _R ^8,

e_d12 ^a _, ⁿ

f_{r R} ^d

o₁ - m₃ ^N _, ^R _R ¹⁵

–_H14 ^R

,_{, R} ¹⁶

6 _-h1 ^;

a_{5,lo R,1 =6,O R,19 -O, RH2,0, -C R21, R22, R31}

1_{-6alkyl, -O-,C R32}

1_{-6a,l Rky3l3, a -nSd-C R34}

1_{-6a alkryel, e -aCc3h-} 6 ^{scuybcslotitaulkteydl, w -Aithr6 f aronmd 1–H toet 36; s wubhsetrietuinen etsac shele ocfte sadid fro -mC1-–6haalklyol, i–sO oHp,ti -oOn-aClly and independently} ₃₀ ^{C 1-6}

3^{-6cycloalkyl, -He alkyl, -S-C1-6alkyl, -} R _R7

3_{7 a annd}

1_{d R}

-_{6a R28}

l_k38,

y_{, a}

l_{, ar}

-_re

C_{e e}

3 _ea ^t6 _h ^-A -_6ac ^, c_{cyh i}

c_{lo in} ^r

n_d ⁶ a_de ^a l_kep ⁿ y_pe ^d–NR37R38

2 ^;

e_{nnddeennttllyy s seelleecctteedd f frroomm––HH,, - -Ch1a-6loa,lk -yOl,H -,C -3C-6}

1_{c-y6acllkoyall,k -yOl a-Cn1d-6 -aHlkeytl2,: C -S- X1 is selected from–C1-6alkl,y -l-A,r–7O an-Cd1–-6Halekty7l;-,–S-C1-6alkyl-, -C1-6alkyl-NR} ^ly _{3-C1-6alkyl-, -NR3-C1-} ^{35 6 sa}

-_S ^ul

-^bk

C^{sy 1- a6}

1^{tl-i N}

-^t,

6^{u -} a^t _l ^edR

k_yl, ^w3- -^i,

p^{th an}

h_e ^frd

n^o _y ^{m -O}

l_{, a} ^1-;

n ^t _d ^{o w 3he sruebinsti etuaecnhts o sfe slaeicdte -dC f1r-o6amlky–l-ha islo o,p -OtioHn,a -lC anldky iln,d -Oep-Cen1-d6aelnktylyl,} X _-NR33R34

2 _is ^a _{selected fro} ^, _{m–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2-C1- s} ⁶

0 _-Su ^l

-_b ^k

C_s ^y _t ^l- _i-t ^,

6_u - a_t ^N

l_ekd ^R

y_{l, w} ^2- -_ipth ^an

h_{e fr} ^d

n_oym ^-O

l _{a 1} ^-;

n_{d to} ^{w e}

-_{N 3} ^he

R _s ^r

3_u ^e

1_b ⁱⁿ

R_s3t2i;tu ^a _e ^ch _nts ^of _se ^s _l ^a _e ⁱ _c ^d _te ^-C _d ¹ _f-_r ⁶ _o ^a _m ^lky _– ^l- _ha ^is _lo ^o _, ^p _-O ^tio _H ⁿ _, ^a -^l _C ^ly _1- ^a _6a ⁿ _l ^d _ky ⁱ _l ⁿ _, ^d _-O ^ep _-C ^en _1- ^d ₆ ^ently _{4 1 alkyl,} -84- A^{r1, o Aprt4io,n Aarll5y, c Aorm6,p arinsding A 1r7 to ar 3e h eeatecrhoa intodmepse snedleecnttelyd a fro 5m- O to, N 10 a-nmdem S;b eearecdh o afro smaidatic cycle Ar5, Ar6, and Ar7 being optionally and independently substituted with fr Ar1, Ar4, substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- om 1 to 3 5 wherein each of said -C 6}

1^{-6alkyl is optionally and independe alkyl, and–NR19R20; et1 - h,h ntly substituted with from 1 to 3 H a}

e ^Hlo

t^ee;

r^{ot2c,yc Hleet4 h,av Hinegt5, fro Hmet61, to an 3d he Hteetr7oa atorems ea sceh independently a 3- to 10-membered said Het1, Het2, Het4, Het5, Het6, and Het7 is o lected from O, N and S; wherein each of 10 f =rOom, - 1 u}

^{(C t=oO 3)-C su1-b6satliktylents selected from–halop,t -ioOnHa,lly–C an1-d6a ilnkdyel,p -eOn-dCe1n-6talylk syul,bs -Stit-uCt1e-6da wlkiythl, indep d tly btit,t aend -NR21R22; wherein each of said -C1-6alkyl is optionally and Het8 is a 3- t 10- b edd h weittehro frcoymcle 1 h toav 3in -hga flroo;m 1 to 3 heteroatom}

1^{5 ad s selected from O, N wn}

w^he

w^{hher S}

r^e;

e^{iinn a wth leenas Rt1 o inse– oHf, s tahiedn h aette leroaastto omnes i hse atettraocahtoemd t oof X H1e ot8r i Xs2 a;ttached to X2; a} C^{besrteitiunen stasid sel Hecette8d i fsrom op–tihoanlaol,ly -O aHn,d–C in1-d nd su 6aelpkeynl,d -eCn1t-6lyalk syulebnseti,tu -tCe1d-6a wlkiythl-C f3r-o6m 1 to 3} _{20 3-6cycloalkyl, -O-C1-6alkyl, -S-C1-6alkyl, =O, -}

_(C=O)-C1-6a ^{cycloalkyl, -} N _{fR21R22; wherein each of said -C1-6alkyl is opti lly dlk iydl, -pCe1n-6daelknytll-yO s-uCb1s-6taitluktyeld an wdith - Z1, Zr2o,m Z3, 1 Z to4 a 3n -dha Zl5o a;re each independently selected from C and N. 25 7. A p compound of Formula Ia or Formula I or a ste}

s_{traot-e omre pnrtesd 1ru tog, 6 s,a wlth,e hryedinra etea,ch N-oxide form, orre sooislvoamteer t,h tearuetoofm aesr, d reafcineemdic i,n m aentyaobnoelite o,f definitions and provisions as defin oefd sa inid s Zta1,te Zm2,e Zn3ts, Z 14 t aon 6d a Zp5p ilsy. C; and wherein the further}

_{30 A 8.}

R_{1 A compound as defined in one of statements 1 t}

1 _{a isn sde Ale2c atered e frach independently selected from Co an 3d w Nh;erein R5 is selected froomm––HH, a -nhda–halo;}

R_{2 is selected from–H a lo and -C1-6alkyl; 35 R3 is selected from–H anndd - -C1-6alkyl;}

X _X1

2 _{i iss sel}

8 _{i sse aleec}

3_ctted

-_{e td f}

o _{from -C1-6}

1_ro0m–

-_{m -O}

e_Cm1-b6aelrka

e_{ylC1-6alkyl; dlk-y,l}

h_–-,

e_{O - te-N}

r_CR3

o_c1-y6-aC

c_{ll1-6alkyl-, -NR3-, -O-;}

H_{et eky}

,_;l

- _w-,

O_{h - HeN}

,_{rRe2-C1-6alkyl-, -NR2-, -On-;}

3 _{substituents selected from–halo –inC s1-a6aidlk Hyle,t8 -C is1-6 oapltkioyleanlely, s -uCb3s-6tcityuctelodal wkyitlh, 1 -C t1o- 40 Z} ⁶

1_{, Z2} ^a _, ^lk _Z ^y ₃ ^l _, ^-C _Z ^3-6

4 _a ^c _n ^y _d ^cl _Z ^o ₅ ^al _a ^k _r ^y _e ^l, _e ^-(C= _h ^O _C ^{)-C1-6alkyl, and -(C=O)-C3-6}

^{cycloalkyl ; and} -85- 9 ^{A.1 A an cdom A2po aurend ea acsh d ienfdineepden inde sntatltyem seelnetct 8ed wh ferein 5 R1 is select rom–H and–h rom C and N;}

R ^R5

2 ^{i ed f}

i^{s sele alo;}

s ^{cted from–H, -halo and -C1-6alkyl;}

R ^{selected from–H and -C1-6}

3 ^{is selecte alkyl;}

X_{1 is selected} ^d _f ^f _r ^r _o ^o _m ^m _– ^– _O ^H- ^{and -C1-6alkyl;}

X _{is selected from–O-CC1-6}

1_{-6aallkkyyll--,, - -NNRR3}

2_--CC1-6

2 _{1-6aallkkyl-, -NR3-, -O-;}

1_{0 Het8 r- 3 is su ab 3s-tit tuoe 1n0ts-m seemlecbteerded fro hmete–rhoaclyoc,le -O;H w,hy}

–_el

C_e,

1_{i - -nN}

6_{a sR}

l_ka2

y_{i-d, - l, HO}

-_{Ce- 1t;8}

-_{6a islk oypletnioen,a -lCly3- s6ucybcsltoitaultkeydl, w ainthd 1 -C t1o-} Z ⁶

1^{, Z2a,lk Zy3l,-C Z3-6}

4 ^{acnydcl Zo5al akryel; e aancdh C.}

1^{5 10. A compound as defined in statement 8 or 9 wherein A1 is N and A2 is C.}

1_{1.A pr ceodmrupgo,u snadlt, o hfyd Froartme,u Nla-o Ixaide or fo arm s,te orre sooislvoamteer th,e traeuotof,mer, racemic, metabolite, pro- or}

^{20 W in}

^I

R ^{R1h R5 iesr 2 i is se s ae}

s^ettl

l^ae

e^cc

c^hte

t^eed

d^{d f}

f ^tr

r^oom

o^{m Z1–}

– ^aH

H^{nd an}

a ^{isd s–ehleclte;d from–H and -C1-6alkyl;}

R^{3 is selected from–H anndd - -CC1-6}

1^-6aalkyl;

2^{5 X X1}

2 ^{is se om}

t ^is ₈ ^s _is ^{elleec d}

a^cttee ₃ ^{d f}

- ^fr

t^r _o ^{om–O-C1-6alkyl-,l -kNyRl;3-C1-6alkyl-, -NR3-, -O-;}

H_{e 10} ^–-^O _m-_e ^C _m1-b6 ^a _e ^l _r ^k _e ^y _d ^l-, _N ^-N _-c ^R _o2n ^-C _ta1i-n6 ^a _in ^lk _g ^yl _h ^-, _e -_t ^N _er ^R ₂ ^{-, -O-;}

s_{ub-6sctyitculoteadlk wyli,th -O 1-C to1- 36a slkuybl,st -iStu-eCn1-t6sal skeylle,c =teOd, f -r(oCmoc}

=_O–y

)_{hcle; wherein said Het8 is optionally C3 -aCl1o-6,a -lOkyHl,, -–CC1-6}

1_{-6aalklkyyl-l,O --CC1-6}

1_{-6aallkkyyllen aen, - 30 Z1, ZN2R21}

3_{R, Z22}

4 _{; a anndd d - , Z Z5 are each C.}

-86- 12. A compound selected from the list comprising:

C_{p d N1 E pl N1 Cp d N2 E pl N2 Cp d N3 E pl N3 Cp d N4 E pl N4 Cp d N5 E pl N5 Cp d N6 E pl N6 C}

_{p d N7 E pl N7 Cp d N8 E pl N8} -87- _C

_{p d N9 E pl N9 Cp d N10 E pl N10 Cp d N11 E pl N11 Cp d N12 E pl N12 C}

_{p d N13 E pl N13 Cp d N14 E pl N14}

C_o

_{p d N15 E pl N15 Cp d N16 E pl N16} -88- _C

_{p d N17, E pl N17 Cp d N18, E pl N18 C}

_{p d N19 E pl N19 Cp d N20 E pl N20 C}

_{p d N21, E pl N21 Cp d N22, E pl N22 C}

_{p d N23 E pl N23 Cp d N24 E pl N24} -89- _Co

_{p d N25 E pl N25 Cp d N26 E pl N26 Cp d N27 E pl N27 Cp d N28 E pl N28 C}

_{p d N29 E pl N29 Cp d N30 E pl N30 Co}

_{p d N31 E pl N31 Cp d N32 E ple N32} -90- _Comp

_{d N33 E pl N33 Cp d N34 E pl N34 Co}

_{p d N35 E pl N35 Cp d N36 E pl N36 Co}

_{p d N37, E pl N37 Cp d N38, E pl N38 Co}

_{p d N39 E pl N39 Cp d N40 E pl N40} -91- _Co

_{p d N41, E pl N41 Cp d N42, E pl N42 Comp}

_{d N43 E pl N43 Cp d N44 E pl N44 Co}

_{p d N45 E pl N45 Cp d N46 E pl N46 C}

_{p d N47 E pl N47 Cp d N48 E pl N48} -92- _C

_{p d N49 E pl N49 Cp d N50 E pl N50 Co}

_{p d N51 E pl N51 Cp d N52 E pl N52 C}

_{p d N53 E pl N53 Cp d N54 E pl N54 C p d N55, E pl N55 Cp d N56, E pl N56} -93-

C_{p d N57 E pl N57 Cp d N58 E pl N58 C}

_{p d N59, E pl N59 Cp d N60, E pl N60 C}

_{p d N61, E pl N61 Cp d N62, E pl N62} C

^{p d N63, E pl N63}

5 -94- ^{13. A compound as defined in statement 11 which is selected from}

C_omp

_{d N46 E pl N46 Cp d N27 E pl N27}

_{Comp d N47 E pl N47}

_{Cp d N43, E pl N43}

_{Cop d N48 E pl N48}

C_{p d N44 E pl N44}

_{Cop d N50 E pl N50}

_{Cp d N45 E pl N45}

_Co

_{p d N49, E pl N49} -95- C

_{p d N59, E pl N59} ^{Cp d N63 E pl N63 Comp}

^{d N62 E pl N62d Cp d N60, E pl N60} _{14. A compound as defined in statement 13 which is selected from} ^.

C_{p d N27 E pl N27 Cp d N44 E pl N44 C}

_{p d N43 E pl N43 Cp d N45 E pl N45} -96-

C

_{p d N59, E pl N59 Cp d N62 E pl N62}

_C

_{p d N60, E pl N60} ^{Cdp d N63 E pl N63} _{15. A compound as defined in statement 12 which is selected from}

_Comp

_{d N60 E pl N60 and}

_Co

_{p d N45, E pl N45.} ^{-97- 16. h Aet ceoromaproylu mndoi aectyco artdi pnogsi ttoio ann Zy1 o inne a occfo srtdaatenmceen wtsith 1 t thoe 1 n1u;m whbeerrienign R as5 i psro linvikdeedd t ion t Fheor amruylla or I 5 or Ia.}

1^{7. Aen caonmtiopmouenr.d according to any one of statements 1 to 12; wherein said compound is the S-}

^{10 18. Aen caonmtiopmouenr.d according to any one of statements 1 to 12; wherein said compound is the R- 19. A to p 1h8a.rmaceutical composition comprising a compound according to anyone of statements 1 15 20. s Ata cteommepnotu 1n9d f aocrc uosredi ansg a to me adniycoinnee. of statements 1 to 18 or a composition according to 21. s Atat ceommepnotu 1n9d f aocrco ursdein ign t tohe an dyioangeno osfis s,ta ptreemveennttison 1 a tnod 1/o8r o trrea atm coemntpo osfit aion LR according to 20 associated disease. RK2-kinase} 2_{2. s Atat ceommepnotu 1n9d f aocrco ursdein ign t tohe an dyioangeno osfis s}

e_{; ,ta ptreemveennts 1 to 18 or a composition accordings teo 25 d aisssoorcdieartse,d su dci tion and/or treatment of a LRRK2-kina hse aass Par wkihnesorenin’s d thiseea LseRR orK A2l-zkhineaimseer’ ass dsioseciaasteed. disease is a neurological 23. d Use of a compound as defined in any one of statements 1 to 18, or a composition as kefined in statement 19, suitable for inhibiting the activity of a kinase; in particular a LRRK2 30 inase.}

2_{4. s Utasteem ofe ant c 1o9m,p foorun thde a dcicaording to anyone of statement 1 to 18 or a composition according to disease. gnosis, prevention and/or treatment of a LRRK2-kinase associated 35 25. m Ae mtheotdho cdom foprri tshineg p aredvmeinntiisotner ainngd/ toor a tre suabtmjeecntt in of a LRRK2-kinase associated disease; said one of statements 1 to 19 or a composition accord nienegd to th setraeteomf aen cto 1m2p.ound according to any}

₄₀ ^{M H}

p^roE

e^mT

d^rpuoO

g^uD

,^{n sd O -98- C asF}

l^{t, o T}

h^fR

y ^fdoE

r^rA

a^mT

t^euM

,^laEN

N^{- (oI)T}

x^{id aend for (mIa,) o ar s sotelvraetoeis tohmereero,f, ta aurteom inehrib,it roarcse omfic L,R mRKet2ab koinliates,e p arcot- or 5 and are thus believed to be of potential use in t treatment of neurological disorders includivinitgy P he}

v^{aasrkciunlsaorn d'sem deisnease, Alzheimer's disease, dementia (including Lewy body dementia and grain disease,t Piaic),k's age related memory dysfunction, mild cognitive impairment, argyrophilic inherited frontotempora dlis deeamse, corticobasal degeneration, progressive supranuclear palsy, 10 withdrawal symptoms/relapsee anstsiaoc aiantded p warikinsonism linked to chromosome 17 (FTDP-17), r Inen thale, b croenatestx,t lu onfg th,e pr porsetsaetent ca innvceenrtsio ans, t wreeallth}

t ^{amse a dr}

n^cu

t^ug

o^{t addiction, L-Dopa induced dyskinesia, and fe P mayrkeilnosgoenn'sou dsis leeukemia (AML).}

o^{f idiopathic Parkinson's disease and familial Parkinson's disease. Inas oene refers to the treatment Parkinson's disease includes patients expressing LRRK2 kinase bearing th eem Gbo2d0i1ment, familial 15 or the R1441G mutation. Treatment of Par 9S mutation d triesaetams kinson's disease may be symptomatic or may be een mt.o Cdifying. In one embodiment, treatment of Parkinson's disease refers to symptomatic as susceptibloem topo punds of the present invention may also be useful in treating patients identified associated with dirsoegarseess piornog tro severe Parkinsonism by means of one of more subtle features cognitive defects, gait or biologeiscsaion such as family history, olfaction deficits, constipation,} _{20 b syiomchpemical, immunological or Im} ^l _a ⁱⁿ _g ^d _in ^ic _g ^at _t ^o _e ^r _c ^s _h ^o _n ^f _ol ^d _o ⁱ _g ^s _i ^e _e ^a _s ^s _. ^e _In ^pro _th ^g _i ^r _s ^es _c ^s _o ^io _n ⁿ _te ^g _x ^a _t, ^ine _tr ^d _ea ^f _t ^r _m ^om _ent ^mo _m ^le _a ^c _y ^ula _b ^r _e ^, I_{n theto cmonatteicxt o orf d tisheea pse modifying.}

o_{f idiopathic Alzheimerre'ssent invention, treatment of Alzheimer's disease refers to the treatment disease may be symptom daitsicea osre m aanyd b familial Alzheimer's disease. Treatment of Alzheimer's 25 A Slizmhielaimrlye,r' tsre daistmeaesnet o reffe dresm toen styiam (pintocmluadte}

i_{inc d triseeaatmseen mt.odifying. In one embodiment, treatment of rel g Lewy body dementia and vascular dementia), age disaetaesde, m ceomrtory dysfunction, mild cognitive impairment argyrophilic grain disease, Pick's dementia andico pbaarskal degeneration, progressive supranuclear palsy, inherited frontotemporal 30 p drisoesatastee m coadnicfyeirnsg. a Isins}

n _wo

o_nen

e_lilsm

e _{ams li}

b _an

o_ck

d_{ue o}

i_{mtde t}

e_{n mt,y c}

t_{ehromosome 17 (FTDP- 7) and renal, breast, lung, rleoagtemneonuts of le duekmemia (AML) may be symptomatic or and vascular dementia), age related memory dysfuenncttiiaon (,inc mluildding co Lgenwy body dementia argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressitive impairment, palsy, inherited frontotemporal dementia and parkinsonism linked to chromosioveme su 1p7ran (uclear 35 1 re7f)e,r and renal, breast, lung, prostate cancers as well as acute myelogenous leukemiaFT (ADP L-) I wnith ths}

d_{e t}

r_{u co}

g_{o sny}

a_tdem

d_xptto

i_{c om}

t_{iofn taht}

a_eic

n _{p tr}

d_re

L_ea

-_st

D_em

o_ne

p_tn

a _int.

i_{vnednutcioend, d tryesaktimneesniat o reffe wristh tdora swymalp stoymmapttiocm trse/aretmlaepnste. associated} ^{Accordingly, the present invention further prov -99- of neu ides a method for the prevention and/or treatment diseasero,lo sgaiicdal m deitshoordde crsom spuch as but not limited to Parkinson’s disease and Alzheimer’s 5 effective amount of a comproisuinndg o ardm ain ciosmteprionsgiti too a subject in need thereof a therapeutic p orpetismeanlt t inrevaetnmtieonnt c caonur bsee u fotirliz aed pa intie ant v,a inrie ptyre odfic steintgtinn tg a}

h^ss

e^{, l iin d}

k^ce

e^llufin

i^hde

o^ind

o^{gd, h}

o ^{feorein. The methods of the fr s euxcacmespsle, in selecting the individual patient with a particular treatment regimen, in assessing disease wh perong trreesastiionng, an monitoring treatment efficacy, in determining pro in 10 predis gnosis for individual patients and in assessing I tnhe trheep}

o^{f ions}

t^hvi

a^eti

t^no

i^tn

n^{io o}

t^nf

h^{, a}

e ^pn

i^{na i}

h^rntiid

b^ci

i^uv

t^ili

o^ad

n^rua

a ^pl

s^{re to}

s^{fae b}

y^reen

f^one

r^cefit

L^{R i fsro}

R^{K gm}

2^{iv ae particular therapy.}

d^{nes tcorib ceodm bpeoluonwds in of Formula I or any subgroup value of less than 10 µM, preferably less than 1 µM, most preferahbiblyit le ksinsa tshean activity with an IC50 Said inhibition may be effected in vitro and/or 100 nM. 15 effect in vivo, and when effected in vivo, is preferably T orhe ot thee}

e^{rdm in}

r ^{d "eL a}

l^{R s}

e^tRe

e^Kle

r^io2ct

u ^kiv

s^ine

c^{a m}

o^snea

d^-nmn

i^tioee

n^{dr,ia a}

i^{ntsed de}

w^{h cf}

i^oin

c^ne

h^{ddi tthi aob"v}

e^no

L^{R oer.}

K ^{"Kd2ise kainsaes"e, a iss u ksneodwn he troein p,la mye aan rosle a.ny Th deise tase "LRRK2 kinase-mediated condition" or "disease" a erm are allevia lso means those diseases or conditions that} ₂₀ ^{the presentted inv beyn ttrieoantm reelnt with a LRRK2 kinase inhibitor. Accordingly, another embodiment of} w_{hich the LRRK2 kinase} ^a _is ^te _k ^s _no ^to _wn ^tre _to ^at _p ⁱⁿ _la ^g _y ^o _a ^r _r ^l _o ^e _l ^s _e ^{sening the severity of one or more diseases in} F _{anodr/ pohra inrm thaece fourtmica ol use, the compounds of the. invention may be used as a free acid or base, obtained with non-tfox aic ph oarrgmaceutically acceptable acid-addition and/or base-addition salt (e.g. 25 and/or complex, and/or in thaen fiocrm or o inro arg paron-icdru acid or base), in the form of a hydrate, solvate a bnyd a un colemsspo outhnedrw oifse th sista itnevde,n thtioen te wrmith“s aol svauittea”g}

b _{iln o}

e_clr

i_{u p}

n_dr

o_ee

r_gs-d

a _ar

n_nu

i_cyg,

s _{c s}

o_ou

l_mc

v_{ebh as an ester. As used herein ninta (teio.gn. w hhyidcrhat mesay be formed solvent, such as but not limited to alcohol ) or organic s s, ketones, esters and the like. Such salts, hydrates, 30 inoslvtaanteces, m etac.de an td the preparation thereof will be clear to the skilled person; reference is for 6,369,086, US-A-o6,3 t6h9e,0 s8a7lts a,nd h UydSra-Ates, solvates, etc. described in US-A-6,372,778, US-A- T fohrem p ohfa wrmaatecre-,ut oicila-slloylu abclcee,p otrab dliesp searlsts-6}

i_{b o,3}

l_{ef7 t ph2}

r_e,73

o_{d cuo3}

c_m.

t_{pounds according to the invention, i.e. in the the quat s, include the conventional non-toxic salts or 35 bases. Eexranmarpyle asm omfo snuiucmh a sacildts a which are formed, e.g., from inorganic or organic acids or b cyecnlzoopaetnet,an beepnrozpeinoensautelf,onate d,igl buicsd}

o_ud

n_lfi

a_ati

t_to

e_en

,_{, s baul}

d_{ttys include acetate, adipate, alginate, aspartate, ordaetec,yls cuitlrfaattee,, camphorate, camphorsulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate e,tha hneexasunlofoantea,te, hy fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesdurlfoocnhalotride, naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionea,t 2e-,} ^{picrate, pivalate, propionate, succinate, tartr -100- salt ate, thiocyanate, tosylate, and undecanoate. Base eartsh in mcelutadle s aamltsmo snuicuhm a salts, alkali mdetal salts such as sodium and potassium salts, alkaline 5 dicyclohexylamine salts, Ns-m caelcthiuyml-D a-gnluc mamaginneesium salts, salts with organic bases such as l syuscinhe a,g aenndts so as fo lrotwh.e Irn a alkdydli htioanlid,e thse, s buacshic a nsit mroeg,}

t^{e a}

hⁿⁿ

y^{-l,cdo s}

e^na

t^htalt

y^is

l^{n,i pn w}

r^gith

o^{p gyr aomino acids such as arginine, l,u apnsd m bauyty ble ch qlouraidternized with and iodides; dialkyl sulfates like dimethyl e, bromides hali , diethyl, dibutyl; and diamyl sulfates, long chain 10 haliddeess l sikuech be anszy dlec aynld, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl s Gaeltnse irnaclllyu,de fo trh peh saurlmfaatece sua p}

t^lh

i^te

c ^en

a^tlhe

u^ath

s^ny

e^ol

,^l–ab

t^{tero amnidde ssulf aanted s oatlhtse.rs. Other pharmaceutically acceptable phar he compounds of the inventions may be formulated as a of them iancveeunttiicoanl a pnredp aatra ltion or pharmaceutical composition comprising at least one compound 15 adjuvant, and optionallye oanset o onre m pohrearmaceutically acceptable carrier, diluent or excipient and/or B adym mineisatnrastio onf, no fonr-lim piatirnegnte erxaalmp aldems, fu}

i^{n srt}

i^suh

t^ce

r^{ahr p}

t^{io aha}

n ^form

(^rsma

u^uc

c^le

h^autitoic

a^nal

s ^mly

b^{a a}

y^yct

i ^biv

n^{ee c}

t^{ra ivnom}

e^{n ap}

o ^fo

u^ou

s^rnds.

,^{m in sturaitambulesc fuolarr or oarl s buyb acnut iamnpeloaus injection or intravenous infusion), for administration by inhalation, by a skin patch, 20 semi-solid onrt, li bqyui ad, su dpeppoesnidtory, etc.. Such suitable administration forms– which may be solid, c} _p ^a _e ^r _r ^r _s ^ie _o ^r _n ^s _; ^, _r ^d _e ^il _f ^u _e ^e _re ⁿ _n ^ts _ce ^an _is ^{d e} _a ^x _g ^c _a ⁱ _i ^{p s o}

n^ieinng

m^t _ad ^f _e ^{onr t}

t ^uh

o^{see m}

f_o ⁱ _r ^nan

i_n ^thn

s^eer

t_a ^p _n ^{r o}

c^ef

e^{p aad}

U^{ramionnistration– as well as methods and} S^t-ⁱ _A-6 ^t _, ^h ₃ ^e ₇ ^r ₂ ^e _, ^o ₇₇ ^f, ₈ ^w _, ^il _U ^l _S ^be _-A ^{clear to the skilled} 6_{,369,087 and US-A-6,372,733, as well as to the standard handbooks, such a-s6, t3h6e9 l,a0t8e6s,t e UdSit-ioAn- o Sf c}

2_{5 l ooo R izme netmnem}

g_{ee pin nsreg ts,fteo , srn care’s recd P ah,h me ba}

t_{ssur ,,tm na lo coc}

a_{ne tioch-lu neimti s,tsita s,inl of eg Sc tli ei}

x_{xeceps ainran}

s_m

d_{, h sl}

a_{ue. rss}

d_{p oef}

g_{n ssuiocnhs, pre epmaurlastiioonnss, in scoluludteion tasb,le stsy,ru ppilsls,, p aeowrodseorlss,, inj elatin capsules, suppositories, eye drops, sterile fore acdtambilneis storalutitions and sterile packaged powders (which are usually reconstituted prior to use) 30 carriers, excipieonnts a,s a and bo dluiluse and/or for continuous administration, which may be formulated with d treaxgtarocsaen,th s,uc groeslaet,in s,orb ciatolcl,n}

i_{u mts}

m_{an thna}

s_iitt

l_{o a}

i_cl,re

a_{t set s}

,_{aurcitable per se for such formulations, such as lactose, mheicsr,oc gruymsta allicnaecia, ce calcium phosphate, alginates, polyethylene glycol, cellulose, (sterile) water, methllyulcloeslleu,lose p,olyvi mnyeltphyyrlr-olidone, propylhydroxybenzoates, talc, magnesium stearate and 35 or suitabl , edible oils, vegetable oils and mineral oils a incvteivnetio sunbe}

)_{s atna m}

d_nixct

o_eu

t_sre

h_{e (swrh th ormulations can optionally c}

s_uice

b_hre

s _{mof. The f}

t_{aany ontain other pharmaceutically ce osr t mhaaty a nroet c leoamdm too a synergistic effect with the compounds of the as lubricating agents, wetting agents, emulsifyinngly an udse sdu isnpe pnhdairmaceutical formulations, such desintegrants, bulking agents, fillers, preserving agents, sweetennging ag aegnetns,ts d,ispersing agents, flow regulators, release agents, etc.. The compositions may also be formulated fl saovo arsin tgo a pgroevnidtse,} ^{rapid, sustained or delayed release of the ac -101- u tive compound(s) contained therein, for example Insin ogrd leiposomesa or hydrophilic polymeric matrices based on natural gels or synthetic polymers. 5 composriti toon en ahcconce tghe solubility and/or the stability of the compounds of a pharmaceutical c cyocmlobdineaxttiroinns wi othrrhi}

a ^td

c^en

y^{icrlo d to}

d^{eerxi tvh}

t^rae

i^{ntiv i}

o^en

r^{svention, it can be advantageous to employ α-, β- or γ- a. d Aenriv ianttievrees tting way of formulating the compounds in particular, the present invention encompassesh aere pohfa hrmasa been described in EP-A-721,331. In effective amount of a compound according to the inventionc weuitthica al p chompaocseitiuotnica clolym apcrciseipntgab alen 10 I cnyc aloddde}

c^{ompoiutx arm}

i^notr

dⁿⁱⁿ

s^,.

. ^{c Ion-s thoelve pnretspa sruactihon as of a alcqouheoolsus m caoym ipmopsriotiovens t,h aed sdoilubility and/or the stability of the the invention can be more suitable due to their increased waterti soonlu obfil salts of the compounds of For local administration, the compounds may a ity. 15 ointmen dvantageously be used in the form of a spray, intradermta olr ad tmrainnsisdtermal patch or another suitable form for topical, transdermal and/or M coomre in particular,ra thtieon c.ompositions may be formulated in a pharmaceutical formulation compproising a therapeutically effective amount of particles consisting of a solid dispersion of the 20 polymeurnds of the invention and one or more pharmaceutically acceptable water-soluble T} _ga ^h _s ^e _eo ^te _u ^r _s ^ms.

s_t ^" _a ^a _te ^s ₎ ^o _c ^li _o ^d _m ^d _p ⁱ _r ^s _is ^p _i ^{ersion" defines a system in a solid state (as opposed to a liquid or} o_{r less evenly throughonugt a thte le oatshte two components, wherein one component is dispersed more components is such that the systrem com ispo chneemntic oarlly components. When said dispersion of the 25 throughout or consists of one phase as defined in the armndod pyhnyasmiciacslly uniform or homogenous r ceofmerpreodne tnots as th "eare sinolid ar seol uustiuoanl"l.y S roelaiddil syolu btiiooanvsai alareble pre tofer trheed o prhgyas,}

n_{i scu}

i_sac

m_lh

s _{sy as solid dispersion is totem wshic bheca thuse the admain ey are It myis ftuerrtehde.r be convenient to formulate the compounds in the form of nanoparticl 30 have a surface modifier adsorbed on the surace thereof in an amount sufficient to maeinsta wihich e f}

b_{f tive average n an efec se particle size of less than 1000 nm. Suitable surface modifiers can preferably includelec vtaerdiou frsom known organic and inorganic pharmaceutical excipients. Such excipients Preferred surface po mlyomdiers, low molecular weight oligomers, natural products and surfactants. 35 Yet another interestingfi wearsy i oncfl fuodrmeu nloantiinogni tch aen cdo amnpioonic surfactants.}

p _{ahnadr ampapclyeiuntgic tahlis co mmixptousreiti aosn a w choearetb fiylm th oeve cro mmapnoyun sdmsun}

a _ad

l_{lr bes a}

e _ianc

d_cc

s_{oording to the invention involves a ,rp thourasted in hydrophilic polymers good bio-availability which can conveniently be manufactured a yniedld winhgic ah co imposition with preparing pharmaceutical dosage forms for oral administration. Materials suitabsle su foitable for cores in the beads are manifold, provided that said materials are pharmaceutically acrce upsteab ales} ^{and have appropriate dimensions and firmn -1e0ss2- inorgani . Examples of such materials are polymers, The prepca sruabtisotnasnc measy, o brega pnric substances, and saccharides and derivatives thereof. 5 least one compound accoerdpianrged to in t ahe ma innvneer known per se, which usually involves mixing at a coccmeppotaubnldes, c wahrreienrs n,ec aensds,ar iyf u dnedseirred a,se ipntic c con}

o^mtio

n^bn

d^{iintia w}

o^tniioth

s^{n th}

. ^{R we}

e^{ifteh on}

r^{en oe}

c^{th or more pharmaceutically eer is p ahgaarimna mceautical active 6,372,778, US-A-6,369,086, US-A-6,369 de to US-A- men ,087 and US-A-6,372,733 and the further prior art 10 Remtiinognteodn’s a Pbohvaerm,a acseu wtell as to the standard handbooks, such as the latest edition of T behe su pihtaabrmlya pcaecuktaicgaeld p,re fopraic}

e^raal

x^{tai Somnci}

p^sen

l^{e ocfe}

i^{n ths}

a^e.

b ^{inovxe,n r}

s ^{btliiosnte ar,re vi pal,e bfeortatlbel,y s ianc ahe utn,i atm dopsoauglee o forr imn, a annyd o mthaeyr oupittiaobnlaelly si wnigle-doese or o mro mreu lleti-adfloestse c hoonltdaeinr or container (which may be properly labeled); 15 Generally, suthch on un ing product information and/or instructions for use.}

5^{40000 m mgg, p oefr t uhneit a dto leit}

s^{a d}

a^so

g^ts

e ^oa

.^{ngee cso wmilplo cuonndta oinf t bheetw ineveennt 1io ann,d e.1g0.0 a0bo mugt, 1 a0n,d 25 u,s 5u0a,lly 10 b0e,tw 20e0e,n 3500 an odr T trhaens cdoemrmpaolu,n sdusbc cuatnan beeou asd,m inintriastveerned by a variety of routes including the oral, rectal, ocular,} ₂₀ ^{on the specific preparation used ando thues, c ionntramuscular or intranasal routes, depending mainly} i _{wnitlrla gveenneoruaslly ad bmein aisdtmraintioisnte uresdua ilnly a bnein“egff percetif} ^d

v_e ⁱ

e_r ^t _r ^io _e ⁿ

a_d ^{to be treated or prevented, and with oral and} m_{.o Tuhnet” a,t b least one compound of the invention compound of Formula or any subgroup thereof that, upon suyit wabhliech ad ism miniesatrnt any amount of a achieve the desired therapeutic or prophylactic effect in the individuaatilon t,o is w suhfificient to 25 administered. Usually, depending on the con ch it is a bdomdyin dition to be prevented or treated and the route of wisetrigahtito dn, such an effective amount will usually be between 0.01 to 1000 mg per kilogram and 250 mg,a foyr o efx thaem ppaletie anbto puetr 5 d,ay, more often between 0.1 and 500 mg, such as between 1 weight day of the patient per day, w 1h0ic,h 20 m,a 5y0 b,e 10 a0d,m 1in5i0s, 200 or 250 mg, per kilogram body over one or more daily doses, or essentially continuoutselyre,d e a.gs. a us siinngle daily dose, divided 30 a bmeo duentet(rsm)i tnoe bde b aydm thineis ttreeraetdin,g th celi rnoicuitaen o,f d aedpmenindisintrgat oionn f aancdto trhse s fuurcthhe arg}

s _{tre a}

t_{haetm dr}

a_{eip infusion. The gnet, re ggeinmdeenr m anady g treenaeteradl. R coenfedition of the patient and the nature and severity of the disease/symptoms to be A-6,372,733r aenndce th ies a fugratin made to US-A-6,372,778,US-A-6,369,086, US-A-6,369,087 and US- 35 s I t}

b_nuc

e _ah

a_{cdc a}

m_{osrid th}

n_ae

i_{sntec laete}

r_{ed wsit sh ed}

e_{p tihti}

a_{eonh ra m oe teefr lyth R p aoer tdmio d oirn a iffgr fe ttt mentioned above, as well as to the standard handbooks, ho}

r_een’

n_{t psr P}

t_eimshea

e_nrm

s_{t d ianc}

u_ve

r_ieu

n_nt

g_tiicoa

t_hnl

e_{, S sc}

c_aienc

o_{idurs pe}

e_hsa.

o_{rmf tahceeruapticya olr co cmonposition can divided or single combination forms. The present invention is therefore to be undceurrsrteonotdly a ins} ^{e "amdbmraincisintegrin agl"l is su toch regimes of simultan -e1o0u3s- or alternating treatment and the term F suoirta abnle o ardadli atidvmesin,i ssut brcae}

h^{ti ion}

a^nter

s ^{e fpor}

x^re

c^mte

i^p,d

i^{e th a}

n^ecc

t^{s, co}

s^or

t^mdi

a^bpn

i^og

l^isly

z^{iet.irosn,s or o ifne thret d pilrueesnetnst, a innvden btriooung chatn by b mee mainxsed of w tith 5 c cuasptsoumleasry methods into the suitable administration forms, such as tablets, coated tablets, hahrde arabic, m,a agqnueesioau,s m,a aglcnoeholic, or oily solutions. Examples of suitable inert carriers are gum particular, corn starch. Ins thiuism ca csaerb,o tnate, potassium phosphate, lactose, glucose, or starch, in 10 granules. Suitable oily excipients or shoelv pernetpsa araretio vne can be carried out both as dry and as moist o sorl cuotidon lsiv,e orr o mili.x Stuureitasb thleer seoolvf.e Pnotsly feotrhy alqeuneeo gulsyc oorls ag}

a^lce

n^ot

d^ha

p^ob

o^{lliec o}

l^{yp sr}

r^{o a}

o^lun

p^{timal oils, such as sunflower oil yiolennse a grle water, ethanol, sugar further auxiliaries for other administration forms. As immediate ryecloelass aere ta ablsloet us,se tful as compositions may contain microcrystalline cell hese 15 steara ulose, dicalcium phosphate, starch, magnesium lubricatnets a knndow lanct ionse and/or other excipients, binders, extenders, disintegrants, diluents and W achceonrdi andgm tionistered th bey ar nt.asal aerosol or inhalation, these compositions may be prepared prepared as s teocluhtnioiqnuses in w seallli-nken,ow emnp in the art of pharmaceutical formulation and may be 20 absorption promoters to enhance bioalovyainilagbi blietyn,zy fl alcohol or other suitable preservatives, d} _th ^is _e ^pe _fo ^r _r ^s _m ^ing _of ^ag _a ^e _e ⁿ _ro ^ts _so ^k _ls ^no _o ^w _r ⁿ _s ⁱ _p ⁿ _ra ^t _y ^h _s ^e _a ^a _r ^r _e ^t. _, ^S _fo ^u _r ^ita _e ^b _x ^l _a ^e _m ^p _p ^h _le ^a _, ^rml

s^au

o^co

l_u ^{ero ns}

t^uc

i_o ^t _n ^iac _s ^arb

,^lo

s ^fo _u ^r _s ^{m, and/or other solubilizing or} p_e ^u _n ^la _s ^t _i ⁱ _o ^o _n ⁿ _s ^{s f} _o ^o _r ^r _e ^{administration in} c_{ompounds of the invention or their phy mulsions of the ac siologically tolerable salts in a pharmaceutically 25 forcmeupltaatbiolen s coalnve anlst, such as ethanol or water, or a mixture of such solvents. If required, the emulsifiers and staboiliz aedrdsit aionally contain other pharmaceutical auxiliaries such as surfactants, F suobrs stuabnccuetsan ceuosutosm aadrmyin thisetrs s}

r_{a w}

e_tfiooe

r_nll

e_{, a t shue a}

c_{h c poromp}

a_speoll

s_ua

o_nn

l_{udt. according to the invention, if desired with the brou bilizers, emulsifiers or further auxiliaries are 30 lyophgihlizte indto an sdolu thteion ly,o suspension, or emulsion. The compounds of the invention can also be i anlfcuoshioonls, pr ee.gp.ar eatthioannso.l, Sp}

p_uh

r_ii

o_tlaiz

p_ba

a_lnetes

o _{sl,o olbtained used, for example, for the production of injection or gvleynctes are, for example, water, physiological saline solution or mannitol solutions, or alternatively mixrtoulr,e isn o afd tdhietio vn also sugar solutions such as glucose or solutions or suspensions may be formulated accordianrgio tuos k snoolvwennt asrt mentioned. The injectable parenterally-acceptable diluents or solvents, such as mannitol, 1,3-b,u utasninegdio suitable non-toxic, 35 s aogleuntitosn, s ourc ihso atosni scte sroiled,iu bmla cnhdl,or fiixdeed so oliulst,io inn, or suitable dispersing or wettingl, a wndate sru,s Rpeinngdeinr'gs aci cluding synthetic mono- or diglycerides, and fatty W mihd}

x_es

i_{nn, i}

g _rn

t_ec

h_cl

e_tuad

c_lli

o_yng

m _{apd o}

o_mle

u_ii

n_nc

d_{is a}

s_tcei

a_rd

c_e.

c_{do irndi tnhge t foor tmhe o infv seunptpioonsit woirtihes a, s thueitsaebl feor nmounl-airtriiotantsin mga eyxc biepie pnret,p saurecdh b ays} ^{cocoa butter, synthetic glyceride esters or - p1o0ly4- temperatu ethylene glycols, which are solid at ordinary In preferrerdes e,m bbuotd liqimueenfyts a,n thde/or co dmisspooluvne in the rectal cavity to release the drug.} _{5 p} ^{ds and compositions of the invention are used orally or} T_a

e_xhr

a_een

m _it

p_ne

l_vr

e_ea

s_nlly

,_{t wi.ohnich w dillo n noowt lim beit th ilelus stcroapteed of b tyhe m inevaennstio onf in th aeny fo wllaoyw.ing synthetic and biological}

^{EXAMPLES -105- A. Compound synthesis and physicochemical properties}

5 ^{T prhoece csosmespo cuonmdmso onfly t uhsised in bvyen thtioosne c saknille bde i prepared by any of several standard synthetic generally prepared from starting materials wnhi tchhe art of organic chemistry. The compounds are by standard means obvious to those skilled in the a arret either commercially available or prepared 10 F}

p ^cho

r^{orrom s}

c^edao

u^{tmoreger waip co}

t^{hhmypounds that were purified by r.eversed phase high-performance liquid HP (HLCPL mCe)th thoed A used method is described below (indicated in the compound person skilled in the art to obtain). a W mhoerne n oepctiemsasal rrey,su thlte fsoer m theet sheopdasr caatinon b.e slightly adjusted by a}

₁₅ ^H

H _Th ^P

P_e ^LC

L_{C cr} ^m

s_uyd ^e

s_e ^tho _p ^d _ro ^A _{duct was purified by reversed phase HPLC, using a Gilson semi-preparative The pur tem operated by Gilson UNIPOINT software.}

5_{µm paritfiiccaletsio)n at w raos carried out on a Phenomenex Luna column (100 mm long x 21.2 mm i.d.; 20 was performed fromom 32 te%mp (erature, with a constant flow rate of 20.0 mL/min. A gradient elution 1 m:1in)ut teos.4 T%he (2 U5V m deMtec NtoHr4 wH2}

a_C5

s_{O m}

s_3M

e_{t a toq NuH}

2_e4

2_oH

6_unsCO

m_{, s3}

w_{olhu aqueous solution) / 68% (Acetonitrile-Methanol itciohn c)o /r 96% (Acetonitrile-Methanol 1:1) in 20 absorbance observed for the compound. responds to the wavelength of maximum}

_{25 A G}

f_osen

r_{m ineral schemes:}

u_{dlicated herein before, the present invention in general provides compounds according to diseasaes I:, for use in the diagnosis, prevention and/or treatment of LRRK2-kinase associated}

^{(I) W} _co ⁱ _m ^th _p ^r _o ^e _u ^fe _n ^r _d ^e _s ⁿ _c ^c _a ^e _n ^to _be ^th _r ^e _ep ^g _r ^e _e ⁿ _s ^e _e ^r _n ^a _te ^l _d ^re _b ^a _y ^ct _f ⁱ _o ^o _r ⁿ _m ^s _u ^c _la ^h _s ^{em -1}

I_a ^e0

o^s6

r ^s- I^u _b ^it _r ^a _e ^b _s ^l _p ^e _e ^f _c ^o _t ^r _iv ^p _e ^r _ly ^e _, ^p _f ^a _o ^r _r ^{ing said compounds, these} s_{chemes can be found herein below. which the general reaction}

5

^{(I) (Ib)}

G

1^{0 In generl h}

a ^{ompounds of formula (I) can be prepared as shown in scheme 1 below wherein} w_hi ^p _th ^{yr al t}

a^az _c ^o _o ^l _m ^{o[1he c}

p_o ^,5 _u-_n ^a _d ^]py _o ^r _f ^im _fo ⁱ _r ^d _m ⁱⁿ _u ^e _la ^or _(II ^a _I) ^im _in ⁱ _t ^d _o ^a _a ^zo _c ^[ _o ² _m ^,1 _p ^-f _o ^]p _u ^y _n ^r _d ^ida _o ^z _f ⁱ _f ⁿ _o ^e _rm ^o _u ^f _l ^f _a ^or ₍ ^m _IV ^u ₎ ^l _, ^a _w ^(I _h ^{I) is converted by reaction} (_{aente breo- c)yacrylilze odf f toorm fourmla a (V c)o tmop foourmnd a o cfo fomrmpouuland (I) o.f formula (VI). The cicohm ipso tuhnedn o refa focrtemdul wait (hVI a c ) 15}

_{Scheme 1} ^-107-

I^{n the above scheme:}

5 ^{L XG1}

3 ^{a anndd L XG2}

4 ^{t eoagcehth ienrde wpiethnd tehnetly fu renpctrieosneanlt m suoitiaebtyle t loea wving or functional groups; unprotected or a protected functional group wh hich they are attached represent an together X1 as defined in formula I ich upon reaction (after deprotection) produce 10 E (he reteprroe-s)aernytls g aro suupit aanbdle th fuen scctiaofnfoall;}

d^{. group that can be used to form a direct bond between the I lena tvhineg a gbroovueps re LaGct1io annd of LG th2e a compound of formula (II) with the compound of formula (III) the} 5 _{group. The reaction ca} ^{re advantageously a halo group such as a chlorine or a bromine} _{1 f aoprpmruolpari (aItIe) w biathse th seu ccohmn}

a_{p b}

s_{oeu a}

f_onf

r_dfe

e _oc

x_fte

a _{fmodrpm by}

l_{eul aa s}

t_{ri (eIu}

t_IIb

h_)s

y _ilntitu

a_{m atnio}

i_{ne onrg fo}

a_ar

t_{n e}

a_icxam

n _{s eolelvp}

v_ele

a_{ntet b}

d _{syu t}

t_cre

e_ha

m _ati

p_sng

e_{r ahe}

a_{c t}

t_{eutroen ciotrmilepo wuinthd a onf under re for example Compoufnludxs. of formula (III) can be obtained through vario}

2_{0 standard m us selective reaction steps by T ahe reactioenans of ob tvhieous co tom tphoousned ski (lIlVed) in w tithhe a art. (hetero-)aryl compound of formula (V) is odfvan thtaegeo (uhseltyer eoff-e)acrtyeld th croomugphou thned cou upnldinegr of S au bzourkoinic c aocniddi Etio onrs bor uosniincg este forr E d eexriavmatpivlee} ^{t (eXtprahkoiss)(tr aipndhe pnoytlapshsoiuspmhi pnheo)psaplhlaadteiu tmrib(0a)s,ic i 2- -d1i0c8y-clohexylphosphino-2’,4’,6’-triisopropylbiphenyl elevated temperature for exa n a solvent mixture such as 1,4-dioxane/water at an 5 c The cyclisation of the compomunpdle o ufn fdoermr ruelfalu (xV.I) can be effecte}

m^{oixntduitrieon ssuc uhsi ansg 2 f-omre etxhayml-1p,l4e-d diisopropyl azodicarboxylate andd tri fpohre enxyalpmhpolsep uhnindeer in M aits suonlvoebnut The res} _l ^u _ky ^lt _l ⁱⁿ _g ^g _ro ^c _u ^o _p ^m _. ^{pou ioxane and toluene at an elevated temperature such as 90°C.} a_{s an a} ^{nd of formula (I) can optionally be treated to introduce substituents such} _{10 I an p gyernaezoralol[ t1h,e5- cao]pmypriomuinddinse o ofr fo arm imuildaa (zI)o[ c2a,1n-f b]epy prirdeapzared as shown in scheme 2 below wherein with a compound of formula (VII) into ine of formula (II) is converted by reaction into a compound of formul a compound of formula (VIII), which is then transformed 15 compound oI)f. formul a (Iv) and reacted with a (hetero-)aryl of formula (V) to form a of formula ( a (VI). The compound of formula (VI) can be cyclized to form a compound Scheme 2}

2^{0 In the above scheme:}

L _XG1

5 _{is a cnodn LveGr2te eda icnhto in ade fupnecntidoennatlly gr roeuppre Xse3;nt suitable leaving or functional groups;} ^{X un3p arontdec Xte4d t oorge ath perrote wcitthed th fuenc ftuionctional mo -1ie0t9y- to which they are attached represent an to nal group which upon reaction (after deprotection) produce Eg reetphreerse Xn1t ass a de sufinitaebdle in f fuonrmctula I;}

5 ^{(hetero-)aryl group and the scaiofnfoalld. group that can be used to form a direct bond between the I lena tvhineg a gbroovueps re LaGct1io annd of L tGhe2 a croem apdovuanndta ogfeo foursmlyul aa h (IaI)lo w gitrhou tphe su ccompound of formula (VII) the 10 group. The reaction can be affected b h as a chlorine or a bromine f aoprpmruolpa y a substitution for example by treating the compound of ri (aIIte) w biathse the su ccohm apsou fondr e oxfa fomrmula (VII) in an organic solvent such as acetonitrile with an unde ple triethylamine at an elevated temperature for example C}

1₅ ^stoamndpr

a^{o re}

r^uf

d^nlu

m^dxs.

e^{a onfs f oobrmviouulas t (oV tIhI) can be obtained through various selective reaction steps by} C _{suoimtapboleu pnds of formula (VII) c} ^o _a ^s _n ^e _b ^s _e ^kil _c ^le _o ^d _nv ⁱⁿ _er ^t _t ^h _e ^e _d ^a _to ^rt. _{compounds of formula (IV) by reaction with a The reacrtoiotencte odf o thre unp croomtepcted linker group.}

a_{dvantageously effected throuoguhnd the (IV co)up wliitnhg o af a (h beoteroron-ic)a aryclid c Eom orpo bund of formula (V) is 20 of the (hetero-)arpyl compound under tionsor uosniincg este forr E d eexriavmatpivle t e (eXtprahkoiss)(tr aipndhe pnoytlapshsoius Suzuki condi}

m_{hi pnheo)psaplhlaadteiu tmrib(0), 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl eleva asic in a solvent mixture such as 1,4-dioxane/water at an The ctyecdlis teamtiopner oaftu tre for example under reflux.}

c_{onditions using forhe ex caommppleou dnidiso opfr fooprmylu alazo (dViIc)a crbaon be effected for example under Mitsunobu 25 m Thixetu rreesu sluticnhg a cso 2m-pmoeutnhdyl- o1f,4 fo-drmiouxalane (I) a cnadn to olupetinonea altx aynla etelev aantded tr tipehmepneyrlapthuoresp shuinche a ins a 90 s°oClv.ent as an alkyl group. ly be treated to introduce substituents such}

^{Example N1 -110-} E _{Pxreapmapraletio Nn1 o isf i pnrteeprmareeddia ftoello 1wing general scheme 1.}

5 ^{Apyr mroixlitduinre-2 o-yfl] 2m-(ettehrat-nboultoxycarbonylami}

^{)thyl th ulfonate (1.20 g, 5.01 mmol), [(2S)- potassium iodide (0.99 g, 10.02 l), di arbonate (1.593 g, 15.03 mmol) and overnight. The sol (v1e.n0t8 w1a gs, r 6e.m51ov memdo uln)d iner N re,Nd-udciemdet phryelsfosrumrea,m diidcehlo (3ro2 ml) was stirred at 60ºC} _{10 t thhe}

i_{eel r m}

d_{e:sixi 5dtu}

1_ur

3_ee

m _{w w}

g_aass

o_{f p f}

i_uilt

n_{reifrieedd b oyve rerv Ceerslieted® p.h Tahsee c soolluvmennt c wharosm reamtoogvrae}

Y _{pdh uyn (dHe} ^m

P_r ^e

L _r ^t

C_e ^h _d ^a

m_u ⁿ

e_c ^e _ethd ^wa

o_{d p} ^s _{r Ae} ^a

)_s ^d ._s ^d _u ^e _re ^{d a} _an ^nd _{d LCMS method 2: MtHe+rm =e 2d4ia5t,e R 1T ( =421%.1)65 min}

1_{5 Preparation of intermediate 2}

I ^{mntl)e.rm Theedia mteixt 1ur (e51 w3as mg st,ir 2re.1d0 a mtm rooolm) w taes}

^{dpi tl d i 4rN hydrochloric acid in 1,4-dioxane (6.3} ₂₀ ^{reduced pressure, toluene was add night. The solvent was removed under} p _{LrCoMduSct m weathso odb 1ta:i} ^{ed twice and remo} _f ^v _u ^e _rt ^d _he ^tw _{r p} ^ic _u ^e _ri ^u _fic ⁿ _a ^d _t ^e _io ^r _n ^re _in ^du _th ^c _e ^ed _ne ^p _x ^r _t ^e _s ^s _t ^s _e ^u _p ^r _. ^{e. The}

M_{neHd+ a =s 1 th4e5, H RCTl = sa 0lt.1 a2n8d m usined without Preparation of intermediate 3} -111-

T ^{acoe ato mniitxritluere (6 o.f2 i7nte mrml)e wdaiaste a 2dd (3e0d03}

^{g 210 l) d tithylamine (1.162 ml, 8.36 mmol) in mmol). The reaction mixture was stirre-bd at 80-5°C-h olvern-pigyht. Thloe[1 re,5a-cat]ipoynri mmidine (485 mg, 2.09 5 t} _c ^h _h ^e _ro ^s _m ^o _a ^lv _t ^e _o ^{nt was removed under reduced pressure. The residue was puriixfiteudre b wya fsla csohol ceodlu amndn} a_{s eluentsgr (agprahdyie onvte erl suitliiocna f groeml u 2sin %g t dichloromethane and a 7N ammonia solution in methanol fractions were collected and the solvenot 1 w0as % re omf 7oNve adm umndoenria re sdoulucteion in methanol). The product LCMS method 2: MH+ d pressure.}

1_{0 = 340, RT = 1.548 min}

P_{reparation of intermediate 4}

I^{dnicteyrcmloehdeiaxytelph 3osp (h1i.n7o1-2’ m,4m’,6o’l-)t,riis 3}

^{phydpylbyipphh yyll) (bXphi) (33id mg (,3050.07 m mgm,o 2l).5 a6nd m pomtaosl)s,iu 2m- 15 p 1h0o}

e^,t3sp

r^{ak mha}

i^sl()te

t^{ri a t}

p^nri

h^dba

e^{n ts}

y^hic

l^{pe (}

h^{o m1.}

sⁱ⁰

p^{x8 g}

h^{tuinre, 3}

e^{)p w e}

a^{aq.) were dissolved in a mixture of 1,4-dioxane and water (3:1, T llsad diuemg(a0s)se (3d5 b myg, b 0u.b0b3lin mgm noitrogen gas through the mixture. stirred under nitrogen gas at 80°C for 5 hours. More 3-hydl)ro wxaypsh aedndyel)dbo arnodnic the ac midix (t1u7re5 w mags} ₂₀ ^{1.28 mmol), tetrakis(triphenylphosphine)palladium(0) ,} d _pihcoy

8_sc

0_plo

°_hh

C_aetexy

o_{v tlrp}

e_ibh

r_nao

i_ss

g_ip

h_ch

t_{. (i5n}

T_4o

h_0-2

e _m’,4

r_g’

e_,,6

a _1’

c_{.- t5tri} ^{(17 mg, 0.015 mmol), 2-} i_{o eis}

n_qo.p

m_{)r wo}

i_xep

t_uryelb

r_{e aipdh}

w_de

a_en

s_dy

c _al

o_{n (X}

o_dp

l_{e thho}

d_{es) (16 mg, 0.035 mmol) and potassium at a mnidxtu three w saoslv setnirtre wda usnd reerm noitvreodge unn gdas reduced pressure. The residue was purified by flash colum er using dichloromethane and n chromatography over silica gel 25 f arnodm th 2e % so tlove 1n0t w %as of re 7mNov aemdm a}

u_{o 7nNia a smolmutoionnia in so mluetitohnan ionl) m. Tehthean proold ausct e flruaecntitosns (g wraedrieen cto ellelucttieond Yield: 239 mg of intermediate 4n (d4e0r% re)duced pressure.} ^{LCMS method 2: MH+ = 354, RT = 1.718 min -112-} P_{reparation of example N1}

5 ^A

d^{e sgoalsustieodn o bfy inte brumbebdliinagte 4 ni (tr2o3g9eng, ga 0s.68 thro l) i 2- thyltetrahydrofuran (20 ml/mmol) was azodicarboxylate (400 mg, 2.04 mmol) in toluugehne t (h2e0 m mlixture. A solution of diisopropyl nitrogen gas through the mixture. Both solutions were adde/dm dmroopl)w was degassed by bubbling 10 a in p teorluioedne of ( 27.55 m hol/umrsm aotl) 9.0 T°hCe t moi axt duerega wsassed st sirorleudtio ant o 9f0 t°rCiph foern 1ylp hhoousis}

r^{.peh and simultaneously over Tihnee r (e535 mg, 2.04 mmol) cooled and the solvent was removed under reduced pressure. The residue waacsti pounr mixture was column chromatography over silica gel using dichloromethane and a 7N ammoniaifie sdol buyt flash} ₁₅ ^{methanol as eluents (gradient elution fro o 10 % of 7N ammonia solution in methiao} T_h ^{m 2 % t nn in} T_he ^ol). e _{r persoduct fractions were collected and the solvent was removed under reduced pressure. Yield: 56idu meg w oafs ex paumrifpield by reversed phase column chromatography (HPLC method A).}

L_C

2_{0 ( aMmSp mlee Nth1od (420: e N1 (12%)}

E_{x m MgH,+ 0 =.13236 m,m RoTl) = w 2a.1s3 d2is msoinlved in a mixtu}

a_{4t:1 ro,o 0m.5 t meml)p aenrdat 4uNre h fyodrro 1ch hloourirc. a Tchied i sno 1lv,e4n-dtio wxaasne re (m10ov µel)re}

d _{w of dichloromethane and methanol uansde ardd reed. The mixture was stirred w saith diisopropyl ether and dried under reduced pressure. The productdu wcaesd o pbrteasinseudre a,s tr tithuera HteCdl 25 Y LCielt}

M_{l.dS: 6 m megth oofd e 2x:a MmHp+le = N 3136 (1,5 R%T) = 2.127 min} ^{Example N2 -113-} E _{Pxreapmapraletio Nn2 o isf i pnrteeprmareeddia ftoello 5wing general scheme 1.}

5 ^{t inetret-rBmuetydli-acthelo 3ro (1d.im70et gh,y 5ls.0ila mnemo (0l).9 a0}

^{d g 60 l) dded portionwise to a mixture of ml). The reaction was tithyl i (1.21 g, 12.0 mmol) in dichloromethane (15} a_{qeuous layer was extr} ^s _a ^t _c ^ir _t ^r _e ^e _d ^d _w ^a _i ^t _th ^ro _d ^o _ic ^m _hlo ^te _ro ^m _m ^p _e ^e _t ^r _h ^a _a ^tu _n ^r _e ^e _{. T} ^fo _h ^r _e ² _s ⁴ _ol ^h _v ^o _e ^u _n ^r _t ^s _w ^. _a ^W _s ^a _r ^t _e ^e _m ^r _o ^w _v ^a _e ^s _d ^a _u ^d _n ^d _d ^{ed and the} _{10 p Yrieeslds:u 2re,2 a4n gd o the product was used in the next step without further purification. er reduced LCMS methodf 2 in:t MerHm+e =di 3a5te4, 5 R (T99 =% 2).625 min}

P_{reparation of intermediate 6}

^{15 t (e2r.t2-4Bu gt,ox 4ycarbonyl anhydride (1}

^{18 g 542 l) ddd to a mixture of Intermediate 5 T} _pr ^h _e ^e _ss ^s _u ^o _r ^l _e ^u _. ^ti.o9

Wⁿ³

a ^{w m}

t_e ^am

r^so

w ^sl)

a^t,i _s ^{r 4re-(}

a^ddim

d_d ^u _e ^ne

d^dthey

a^rl

n_d ^ref _t ^li

h^{ux) fpoyri 2di hou (3rs1. Thge, 0 s.2ol5venmto wla)s in re temtrahydrofuran (15 ml).} _{20 de aqueous layer was ex} ^{oved under reduced} o _{rergsiadnuiec w laayser p wuraifsie ddri beyd, fl failstehre cdolu amnn t ch tracted with ethyl acetate. The hero smoalvteongtra wpahsy r oevmerov seilidca un gdeelr us reindguc heedpt parneess aunrde. e Tthhyel} ^{a wceerteat ceol alesct eelude anntsd ( thgera sdoielvnetn etlu wtaiosn re frmomov 0 % -1 to141-00 % of ethyl acetate). The product fractions} Y_{ield: 1.7 g of inter} ^{ed under reduced pressure.} 5 _{LCMS method 2: MmHe+d =ia 5te546, ( R6T2% =) 3.094 min}

P_{reparation of intermediate 7}

A ^{thro muixgthur tehe o mfi 1x,t4u-rdei.o Ixnatneerm aenddi}

^{t 6t (1. (3181 l) dg d by bubbling nitrogen gas 10 ( d5ic0y0clo mhge,xy 3lp.2h4osp mhminool-)2,’,4 te’,t6ra’-ktriisis(toriphe5n0yl gp,ho 2s.7p0hine)pal)l,la (d5i-um(i0)-2 (5-f3lu3or mo-gp,he 0n.y4l6)bo mromnoicl), ac 2id- phosphate tribasic (1.7 g, 3 eq.) wepropylbiphenyl (Xphos) (872 mg, 1.83 mmol) and potassium 85°C overnight. More (r5e-a amdidneod-2 a-fnlud the mixture was stirred under nitrogen gas at} ₁₅ ^{tetrakis(triphenylphosphine)palladium(0) (0.02oro e-qp.henyl)boronic acid (1.2 eq.),} t _{graiisso aptro 8p5y°lbCip ohveenrynlig (Xhtp.h Tohse) ( r0e.0a8cti eoqn.) m wixetruere ad wdae} ^{), 2-dicyclohexylphosphino-2’,4’,6’-} s_{d and the mixture was stirred under nitrogen oergdaunceicd la pyreesrsu wraes. T whaesh reesdid wueith w wasate pru,rif dierided b,y fi fltlae c}

s_{roeoled and diluted with ethyl acetate. The r hd co alnudmn the solvent was removed under 0 using heptane and ethyl acetate as eluents (gradient elution f chromatography over silica gel 2 p Yrioedldu:c 1t. f3r0ac gtio onfs in wteermree cdoiallteect 7ed (8 a2n%d) the solvent was removedro umnd 0e%r r teod 6u0ce%d e ptrheysls aucreet.ate). The}

_{Preparation of intermediate 8} -115-

2 ^{(1-N.3i0tro gb,e 2n.z2e2n mesmuolfol)n,y ply crihdlionreid}

^{(23 (065 µ9l, g 2.62666 l)l)d 4-(ddiddth tyla am solution of intermediate 7 5 mmol) in dichloromethane (6.66 ml). The react ino)pyridine (13 mg, 0.11 o hvyedrrnoicghhlot.ri Dcic ahcliodro smoleutthioann.e ion mixture was stirred at room temperature}

T ^{wheas or agdadneidc l aanyder th wea osrg darineidc, l failyteerre wda asn wda thshee sdol wveithnt a w 1aNs aqueous} u_{nder reduced pressure. The residue was purified by flash colum} ^removed g_{ecelta utsein).g T hheept parnoedu acntd fra ectthioyl acetate as eluents (gradient elutinon ch frroommat 0o%gra tpohy 10 o0v%er s eitlihcya a l 10 Y pressure. ns were collected and the solvent was removed under reduced LCieMldS: 1 m.0e3t3ho gd o 1f: in MteHr+m =ed 7i7a0te, R 8T (6 =0% 1.1)76 min 15 Preparation of intermediate 9}

I ^{3n.t1e2rm mel)di aanted 8 th (e80 m0ix mtugre, 1 w.0a4s}

^{ti dl) t di tlpd i ti id/water/tetrahydrofuran (3:1:1,} c _{uonndceern rterdautecded un pdreerss reudreu.ce Tdhe pr reesssiduuree a wnad} ^{t ight. The reaction mixture was} _{20 s to pluureifnieed w bays fl aadsdhe cdo 3lu tmimne csh arnodm caotongcreanpthrayte odve 3r t similiecas} ^{g soellv uesnitn wga hse rpetmanoeve adnd un edtehryl re adcuectaetde p aress elue -n1ts1.6- The product fractions were collected and the} Y_{ield: 580 mg of intermediat} ^sure.

L_{CMS method 1: MH+ = 656e, R 9T (85%)}

5 _{= 0.830 min}

P_{reparation of intermediate 10}

A ^{solution of intermedia}

1^{0 degassed by bub te 9 (580 g 088 l) i 2 thyltt hydrofuran (20 ml/mmol) was a nz}

p^ietorrod

i^ogic

d^eanrb

o^{f go}

3^axsy

h^{o tlha}

u^{rte bling nitrg g th gh th it . A solution of diisopropyl rosu (}

a^g1

t^h80

9 ^{t0h°e m}

C ^mg,

t^{iox 0t l i}

a^{u.8r de8}

e^{.g B m}

a^om

s^tsho

e ^sl)

d^{o sun}

o^{tiluo tonlu}

t ^{weenree ( a2d0de mdl/ smimmuoltla)n weaosus dlyeg aansds derdop bwyis beu obvbelirng a} t_{oluene (75 ml/mmol} ^{ion of triphenylphosphine (231 mg, 0.88 mmol) in} 5 _{cooled and the solven).t w Thaes r memixtouvreed w uansde srti rreredduc aetd 9 p0r°eCss fuorre 1. T hhoeur r.es Tidhe reaction mixture was 1 c froalcutmionns ch wreormea ctography over silica gel using heptane and ethyl acetateu aes e wlausen ptusr.if Tiehde b pyro fdlauscht YCieMldS: 4 ollected and the solvent was removed under reduced pressure.}

L _{m70et mhogd o 1f: in MteHr+m =ed 6i3a8te, R 1T0 ( =840%.95)7 min}

2_{0 Preparation of intermediate 11} ^-117-

^{T adod aed so cleustiiounm o cfa inrbteornmaetedi (a4t1e11}

^{0g (4,010.26g 06l)3 d thl) i NNdi thylformamide (2.0 ml) were 5 m thiixotpuhreen wolas (0 s.1tirr eeqd.) at w reoroem ad tedmedperature for 17 houris.ph Morel c (8e0siu µml, 0 c.7a6rb monmaotel). (0 T.h5e e rqe.a)c ationdn aqueous sodium hydroxid and the reaction was stirred at room temperature. A 1N} a_{cetate. The or} ^{e solution was added and the water layer was extracted with ethyl} 0 _{pressure. The rgeasnidicue lay wears w pausrif dierided b,y fil ftlearsehd c aonldum thne c shorolvmenatto wgraasph reym oovveerd s uilincdaer ge reld uusced 1 h peropdtauncet fr aancdtio entshy wle arcee ctaotlleec atesd e alunedn tthse (g sroalvdeienntt w ealsut rioenmo frvoemd 0% to 100% ethyl acetate). Tihneg LCMS method 1: MH+ = 453, RT = 0.771 min under reduced pressure. Preparation of example N2}

^{15 I mntl)e.rm Theedia mteixt 1u1re (3 w5a8s m sgti,rr 0e.d79 a mt r}

^{l) t dpi tl d i 4Nig hhytd. Tchhelo sroiclv aecnitd w ina 1s,4 re-dmiooxvaende u (n3.16 red} _e ^u _ss ^c _u ^e _r ^d _e. ^p _T ^re _h ^s _e ^su _c ^r _o ^e _m ^. _p ^D _o ^ie _u ^t _n ^h _d ^yl _w ^et _a ^h _s ^er _ob ^w _t ^a _a ^s _in ^a _e ^d _d ^d _a ^e _s ^d, _th ^th _e ^e _hy ^c _d ^o _r ^m _o ^p _ch ^o _l ^u _o ⁿ _ri ^d _c ^w _ac ^a _i ^s _d ^f _s ^il _a ^te _lt ^r _. ^{ed and dried under reducdeedr} _{20 Y pr}

L_{CieMldS: 1 m00et mhogd o 2f: e MxaHm+p =le 35 N32, R (3T6% =) 1.952 min}

₂₅ ^{Exammpl -118- E} _ill ^x _u ^a _stra ^p _t ^le

e^{e N}

d ^N3

f_o ³ _{r t} ^m _he ^ay _pr ^b _e ^e _pa ^p _r ^r _a ^e _t ^p _io ^a _n ^re _o ^d _{f e} ^fo _xa ^llo _m ^w _p ⁱ _l ⁿ _e ^g _N ^g ₂ ^e _. ⁿ _T ^e _h ^r _e ^al _p ^s _ro ^c _d ^h _u ^e _c ^m _t ^e _wa ¹ _s ^a _o ⁿ _b ^d _ta ^a _in ^c _e ^c _d ^or _a ^d _s ⁱⁿ _t ^g _he ^to _HC ^th _l ^e _sa ^p _lt ^r _. ^ocedures

^{5 E}

E^{xa ple}

i_ll ^x _u ^am

s^m _tra ^p _t ^l _e ^{e N}

d ^N4

f_o ⁴ _{r t} ^m _he ^ay _pr ^b _e ^e _pa ^p _r ^r _a ^e _t ^p _io ^a _n ^re _o ^d _{f e} ^fo _xa ^llo _m ^w _p ⁱ _l ⁿ _e ^g _N ^g ₂ ^e _. ⁿ _T ^e _h ^r _e ^al _p ^s _ro ^c _d ^h _u ^e _c ^m _t ^e _wa ¹ _s ^a _o ⁿ _b ^d _ta ^a _in ^c _e ^c _d ^or _a ^d _s ⁱⁿ _t ^g _he ^to _HC ^th _l ^e _sa ^p _l ^r _t. ^ocedures

₁₀

^{Exa -119- E} _P ^x _re ^am

p^{mple N}

a^p _ra ^le _tio ^N5

n⁵ _o ^m _f ^a _in ^y _te ^b _r ^e _m ^p _e ^r _d ^e _ia ^p _t ^a _e ^re ₁ ^d ₂ ^{following general scheme 2.}

^{5 A am minioxetuthreyl) opfyr 3ro-blirdoinmeo-1-5-c-cahrbloorxoy-playtr}

^{(1l.0[115 g,] 4p.y73i idi l) (10 g, 4.30 mmol), tert-butyl 2-(2- mmol) in acetonitrile (12.9 ml) was stirred unde nd triethylamine (0.878 ml, 5.16 cooled and ethyl acetate was added. r reflux for 16 hours. The reaction mixture was and the solvent was remov The organic layer was washed with water, dried, filtered} _{10 c eo}

o_lulu

l_{timonn f crohmrom 0a %tog troap 1h0y0 o %ver} ^ed

o _sfil ^u

e_ic ^ne

t_a ^d

h_{y g} ^r

l_{e al} ^re

c _u ^d

e_s ^u

t_ain ^c

t_eg ^ed

)_{. he} ^p

T_p ^r

h_t ^e

e_a ^s _n ^s

p_e ^ur

r_{o a} ^e

d_n ^.

u_d ^T

c_{t e} ^h

f_t ^e

r_hay ^r

c_l ^e

t_{i a} ^{si s} s _oc ^d

n_e ^ue

s_{ta wte} ^wa

e_{r aes c e} ^p

o_l ^u

l_u ^r

l_ee ^if

c_n ^ie t_tes ^d

d ₍ ^b _g ^{y a} a_rnadd ^fl _ie ^s t_hn ^h e_{t Yievlde:n 1t. w6a5s4 r gem ofo inved under reduced pressure.}

L _{termediate 12 (94%)}

1_{5 CMS method 1: MH+ = 410, RT = 1.000 min}

P_{reparation of intermediate 13}

I ^{mntl)e.rm Theedi matiex 12 (1.654 g, 4.03 mm}

^{l) di l d i 4N hydrochloric acid in methanol (12.09 20 r} _c ^e _o ^d _m ^u

x_tp ^c

s_o ^e _u ^d _n ^{p u}

d^re _w ^st

a^s _s ^urer _o ^{e w}

b^.a

t_a ^Ts

i^o _n ^{l s}

e^ut

d^eirnre

a^ed

s ^{w a}

t_h ^at

e^{s ro}

h ^ao

y^d _d ^d _ro ^{e t}

c^d _hl ^t _o ^wp

rⁱ _i ^c _c ^et

a ^a _ci ^{n f}

d^d _s ^r _a ^e _lt ^{m 2}

a^o _n ^{v h}

d^ed _us ^t _e ^w.

d^{ic T}

w^ehe

i_t ^u _h ^{n s}

o^do

u^elv

t^re

f_u ^{rnd w}

r^et

t_h ^u _e ^ca

r^es

p^{d re}

u_r ^pm

i_f ^r _ic ^eo

a^sv t^se i_o ^ud n^{re u} i^.n n ^Td t_h ^he e^er

L _ne

P_CreMpaSte

r_{a mp}

t_ie.

o_{tnho odf i 1n:te MrmHe+d =ia 3t4e71,4 RT = 0.287 min} -120-

2^{1-2b.0ro9mo memthoolx)y-t weretr-ebuty ald-ddiemdeth ty}

^{lil (l88ti0 µlf 40 I3t dl)itnd 1 c3esi (u4m.0c3arb monate (3.939 g, dimethylformamide (12,09 ml). T mol) in N,N- 5 a ddicdhelodrom anetdhan thee/me athqauneoolus (9:1 la).yhee}

T^{r rea}

h^{e wc}

o^{ation mixture was stirred at 60°C for 6 hours. Water was rsgan extracted with ethyl acetate and a mixture} r_{emoved under reduced pressure. The resid} ^{ic layer was dried, filtered and the solvent was} o_{ver silica gel using dichloromethane and ue was purified by flash column chromatography % of methanol). The product fractions w methanol as eluents (gradient elution from 0 % to 10 10 redu ere collected and the solvent was removed und Y LCieMldc}

S_{:e 1d}

m_{.2 p}

e_2r

t_7es

h_{o gsu}

d _or

1_fe

: _{in. er MteHr+m =ed 4i6a9te, R 1T4 ( =650%.77)9 min}

P_{reparation of intermediate 15}

^{15 t (e1r.t2-2B7ut go,xy 2c.arbonyl anhydride (0}

^{90 l 393 l) ddd to a mixture of Intermediate 14 ml). The sol6u2tio mmol), 4-(dimethyl i )pyidi (16 g, 0.13 mmol) in tetrahydrofuran (7.86} 0 _{3 a.93 mmo} ^{n was st} _a ^{irred under reflux for 16} _, ^{hours. tert-Butoxycarbonyl anhydride (0.90 ml,} _{2 added andl) t,h 4e-( mdiimxtuerthey wlamsin sotir)rpeydrid aitn 7e0 (°1C6 fo mrg 200 h.1o3ur ms.m Tohl)e a renadc ttrioienth myliaxtmurinee w (a0s.5 c0o2ol medl), w etehr dc yel rieetda,te filt weraesd a adndded the an sdolv theent o wrgaasn ricem laoyveerd w uansde erxt rreadcutecded w pitrhes wsautreer.. Th Tehe res oirdguaeni wca lasy peurri wfieads} ^{b (gyra fldaisehnt co elluumtionn c fhroromma 0to %gr taoph 7y % ov oefr m sileicthaa g - ne1}

o^l2

l^{) u1}

.^{s- Tinhge d picrohdlouroctm ferathcatinoens and methanol as eluents} s_{olvent was remove} ^{were collected and the} Y_{ield: 1.387 g of d under reduced pressure.}

5 _{LCMS method 1: in MteHr+m =ed 5i6a9te, R 1T5 ( =931%.09)5 min}

P_{reparation of intermediate 16}

^{10 A t}

^{s ah}

d^{cr mouixgthur tehe of m 1ix,4tu-dreio.x Iannteerm andditt 15 ( (311.38773 g2, 2.l4)4 dl),g (5-mdin boy-2 b-uflubobrlion-gph neitnryolg)beonro gnaic pihcid}

o^{yscpl (o6}

h^h9

a^e0

t^{exy m}

t^lrpg

i^bh,

a^{o 2}

s^sip.9

c^h3

(^{i1n.o m}

5^-52m

3^’,o4l)

g^’,,

,^{63’ t-et ertir}

q^iask

.^oi

)^ps

w^r(

e^otr

r^pip

e^{yhl abe}

d^inpy

d^hl

e^ep

d^nhyo

a^ls

n ^(p

d^Xh

t^pin

h^he

e^o)

m^sp)a

i^{x (ll}

t^4a

u^8di

r ^{mumg(,00).1 (058 m mmgo,l) 0 a.0n5d p momtaosls),iu 2m- at 85°C for 16 hours. The reaction mixture was cooled e was stirred under nitrogen gas} _{15 o rerg}

s_da

i_nun

g_{ceic a}

d_{d l}

i_{c pry}

h_loee

r_sr

o_{smu wra}

e_es

t_{.ha T w}

n_ha

e_esh

a _rnee

d_{sdid w}

m_ueeith

t_{h w w}

a_ansate

o_{l pru,rif dierided b,y fi fltlaesrehd co aln} ^a

u_d ^nd

m_{n the} ^dil

c_{h s} ^u

r_oo ^te

m_lv ^d _eatn ^w

o_t ^ith

g_{r waa} ^e

p_s ^th

h_{y r} ^y _e ^{l e}

o_m ^a v_eo ^c

r_ve ^ta s_d ^te i_{lic u} ^. a_n ^T _d ^h g_e ^e e_{r u l The product fractions were co as eluents (gradient elution from 0% to 10% methanol). 0 Y LCieMldS: 0 m.9e9th go odf 1 in:t MerHm+e llected% and the solvent was removed under reduced pressure. 2 =di 5a9te9, 1 R6T (6 =81.0)53 min}

P_{reparation of intermediate 17} -122-

2 ^{(0-N.9i9tro gb,e 1n.z6e7n mesmuolfol)n,y ply crihdlionreid}

^{(1 (4084 µ4l, g 1.26700 l)l)d 4-(ddiddth tyla am sionlout)ipoynri odfin iente (rmediate 17 5 mmol) in dichloromethane (5.0 ml). The reaction mixture was stirred a 10 mg, 0.08 h woausrs s.tir Mreodre at 2 r-onoitrmob teenmzpeenreastuurlfeon foyrl 1 ch hlooruidr.e D (i0c.088 g, 0.4 mmol) wast r aododmed te amnpde trhaetur meix foturr 4e was washed with a 1N aqueous hydrochl hloromethane was added and the organic layer} a_{nd the solvent was rem} ^{oric acid solution. The organic layer was dried, filtered} 0 _{column chromatogr oved under reduced pressure. The residue was purified by flash 1 ( wgarasd rieemnto evleudtio unnd freormap}

r_{e 0h}

d_%y

u_{c teo ov}

d _7e

p_%r

r_{e m sil}

s_seic

u_trha

e_{a.n goell). u Tshieng pro ddicuhclto frroamcteiothnasn weer aen cdol mlecettehdan aonld a thse e sloulevenntst Y LCieMldS: 0 m.9e7t5ho gd o 1f: in MteHr+m =ed 7i8a4te, R 1T7 ( =741%.16)8 min}

1_{5 Preparation of intermediate 18}

T ^{(9e2tr5ab mugty,la 1m.1m8o mnimumo fluoride}

^{(189 g 189 l) ddd t solution of intermediate 17} 0 _{t aenmdp aer saattuurreat feodr a 2q4u h} ^l)

e_oou ⁱⁿ

u_rss. ^{tetrhyd f (3.54 l). Th ti mixture was stirred at room} _{2 so Tdhieum m bixictuarrebo wnaaste d siloultuetdion w.it Thh eeth oyrgla anciecta latyee arn wdas w dasriheedd, fi wlteithred wa atnedr} ^{t ahned s dorliveedn utn wdaesr r reemduocveedd p urnedser reduced pres -s1u2r3e-. Acetonitrile was added, the solid was filtered} Y_{ield: 680 mg of intermedi} ^sure.

L_{CMS method 1: MH+ = 67ate 18 (86%)}

5 _{0, RT = 0.804 min}

P_{reparation of intermediate 19}

A ^{in s dorlyut Nio,nN o-dfi imnteetrhmylefodriamteam 1i8d (}

^{5 (820 lg) 08d7 llt)i i 2f ditihyplttpyhly adzroofduicraanrb (o2x0yl matle/mmol) and 10 2 h.o6}

h^u1

e^{rs m}

m ^am

i^xto

t ^9l

u⁰⁾

r^{e° iCn t}

w ^to

a^olu

s ^ae

s ^sn

t^oe

i^{rlru (20}

e^{tdion m}

a^{t ol/fm}

9 ^{tmol) were added simultaneously and dropwise over a pe (5ri2o0d m ofg 2, T 0ri°pChe fnoyrlp 3h0os mpihniuntees (.68 T5he mg re,a 2c.6ti1on mm moixlt)u irn toluene (75 ml/mmol).} s_{olvent was removed under reduced pressure. T} ^{e was cooled and the} 5 _{c ehromatography over silic he residue was purified by flash column 1 l tu}

r_{elumtioovned from 0% to 3% meatha gneoll) u.s Tinhge d pircohdlourcotm freatchtaionnes a wnedre m ceotlhleacnteodl a asnd eheen stsolv (gernatd wieanst YCieMldS: 57 under reduced pressure.}

L _{m4et mhogd o 1f: in MteHr+m =ed 6i5a2te, R 1T9 ( =960%.92)9 min}

_{Preparation of intermediate 20} ^-124-

5 ^T

m ^ado

i^{xd a}

t^{eud so}

r^{e cleu}

w^sti

a^ioun

s^{m o}

s^{t cf}

i^{ra in}

r^erbte

d^or

a^{nmediate 19 (546 g, 0.84 l) i N,N-di thylformamide (2.52 ml) were ta rtoeo (m54 t7em mpge,r 1a.6tu8re m fmoro 3l) a hnodur tsh.io Epthhyeln aocle (1ta0t0e µ wl,a 1s.01 mmol). The reaction layer was washed with a 1N aqueous sodium hydroxid added and the organic filtered and the solvent was re e solution. The organic layer was dried,} 0 _{column chromatography ove} ^m _r ^o _s ^v _il ^e _ic ^d _a ^un _g ^d _e ^e _l ^r _u ^re _si ^d _n ^u _g ^ce _d ^d _ic ^p _h ^r _l ^e _o ^s _r ^s _o ^u _m ^re _e ^. _th ^T _a ^h _n ^e _e ^re _a ^s _n ^id _d ^ue _m ^w _e ^a _th ^s _a ^p _n ^u _o ^r _l ^ifi _a ^e _s ^{d by flash} _{1 ( sgorlavdeinetn wta eslu rteiomnov freodm un 0d%er t roed 1u0c%ed m preetshsaunrol). The product fractions were collected a enlude tnhtes Yield: 206 mg of intermediate 20 ( e.}

L_{CMS method 1: MH+ = 467, RT =532%.36)7 min}

1_{5 Preparation of example N5}

I ^{mntl)e.rm Tehdeiat meix 2t0ur (e20 w6a msg s,t 0ir.r4e4d m}

^{t l) di l d i 4N hydrochloric acid in methanol (1.32} D_{iethylether was added, the compound wa} ^{t p t ight and at 45°C for 6 hours.} _{20 f LoCrM 16S h moeutrhso.d Th 2e: M prHod bt s filtered and dried under reduced pressure at 60°C}

+_{u =c 3t6 w7a,s R oT =ai 1n.e8d80 as m tihne HCl salt.} ^{Example -125- E} _ill ^x _u ^a _s ^m _tra ^p _t ^l _e ^{e N}

d ^N6

f_o ⁶ _{r t} ^m _he ^ay _pr ^b _e ^e _pa ^p _r ^r _a ^e _t ^p _io ^a _n ^re _o ^d _{f e} ^fo _xa ^llo _m ^w _p ⁱ _l ⁿ _e ^g _N ^g ₂ ^e _. ⁿ _T ^e _h ^r _e ^al _p ^s _ro ^c _d ^h _u ^e _c ^m _t ^e _wa ¹ _s ^a _o ⁿ _b ^d _ta ^a _in ^c _e ^c _d ^or _a ^d _s ⁱⁿ _t ^g _he ^to _HC ^th _l ^e _sa ^p _l ^r _t. ^ocedures

^{5 E}

E^{xm e N7}

P^xa

r_e ^a _p ^mpl

a^p _ra ^le

t_io ^N _n ⁷ _o ^m _f ^a _in ^y _te ^b _r ^e _m ^p _e ^r _d ^e _ia ^p _t ^a _e ^re ₂ ^d ₁ ^{following general scheme 1.}

^{10 t (e2r.t0-0Bu gt,yl 1-c9h.7lo7ro mdmimoel)th aynlsdila imneida (4z.o4l7e ( g2,.6299}

e^{action was stirred at room temperature fo26}

r ^g6

7^{,23 h9o.5u4l)}

r^{s. Tmas}

h^{eol a)dded to a mixture of piperidin-4-ol r so inlve dnicth wloarsomethane (59.31 ml).The} p_{ressure. The residue was purified by flash column chromatograph} ^r _y ^em _ov ^o _e ^v _r ^ed _si ^u _li ⁿ _ca ^de _g ^r _e ^re _l ^d _u ^u _s ^c _i ^ed _{15 p dichloromethane and methanol as eluents (gradien anol). Tnhge LrCoMduSct m freathctoio t elution from 0% to 10% meth}

d_{n 1s: w MeHre+ = co 2ll1e6c,te RdT a =nd 0. t5h1e6 s molivnent was removed under reduced pressure.}

_{Preparation of intermediate 22} ^-126-

^{A pot masixstiuurme c oafrb ionnteartmee (d2i1a.t8e62 g1, 1 (5189.1.767}

^{l)l) 2b oethanol (2.81 ml, 39.54 mmol) and 5 W dicahtelorro wmaesth aadndeed an adnd m the aqueous layer wa is extrtactietrdile w (i5th9. e3t1hy mll a)c iset raetfelux aendd f aor m 2i0xt huoreur os.f removed under reducee pthreasnsoulr (e9.:1 T)h.e Th rees oidrguaen wica lsay peurr wifiaesd d bryied fl,as fihlte creodlum annd c thhero smoalvtoent was} o_{ver silica gel using dichloromethane and methanol as eluents (gradi} ^graphy 0 _{m prethanol). The product fractions were collected and the solvent waesnt re emluotivoend fr uonmde 0r% re todu 1c0e% 1 Y LCieessur}

M_{l e. d dS: 3 m.0e6th go odf 1 in:t MerHm+e =di 2a6te0, 2 R2T (6 =0% 0.6)01 min}

P_{reparation of intermediate 23}

^{15 Sbroodmiuom-5- hcyhdlorirdoe-p (y6r0a%zo ilno[1 m,5in-ear]aply}

o^{l) in dry N,N-dimethylformamiil}

i^{did 1}

eⁱ⁵⁵

(^{19 (1g}

.^3.5506

m ^g4,5

l^{) 6.. T45 l)}

h^{e realc) d}

t^{iondd iendter amte 0d°Ciat teo 2 a2 s (o2l.u0t1io gn, o 7f.734- mm}

2_{0 temperatu} ^{mixture was stirred at room} A _{ext sraactuteradter}

w_{de f}

i_{th aoqr}

e_{u 1}

t_{he h}

y_oo

l_uu

a_sr.

c_{e atmatmeo annidum a m chixloturirdee of so dliuchtiolonro wmaestha andede adnd an mdet thhaeno alq (u9e:1o)u.s Th laeye sorlv weanst} ^{warsom raetmogorvaepdhy u onvdeerr sil riceadu gceeld us pinregs hsuerpeta. -127- ch ne Th aend re esthidyule ace wtaatse a psur eifliueednts by (gr faladsiehnt c eolluumn from 0 % to 7 % of ethyl acetate). The product fractions were collected and the solv tion} 5 _{removed under} ^{ent was} Y _{LCie reduced pressure.}

M_{ldS: 1 m.6e8t8ho gd o 1f: in MteHr+m =ed 4i5a6te, R 2T3 ( =570%.88)0 min}

P_{reparation of intermediate 24}

^{10 A thr mouixgthur tehe of m 1ix,4tu-dreio.x Iannteerm anedd}

^{itt 23 ( (311.210 l) dg d by bubbling nitrogen gas acid (0.99 g, 4.19 mmol), tetrakis( 588 g, 3.49 l), (5-mino-2-fluoro-phenyl)boronic dicyclohexylphosphino-2’ triphenylphosphine)palladium(0) (81 mg, 0.07 mmol), 2-} ₁₅ ^{phosphate tr ,4’,6’-triisopropylbiphenyl (Xphos) (67 mg, 0.14 mmol) and potassium} a _{otrg 85°C for} ⁱ ₁ ^b ₆ ^as _h ^ic _ou ⁽² _rs ^.2 _. ² _T ² _h ^g _e ^, _r ³ _ea ^e _c ^q _t ^. _i ⁾ _on ^we _m ^re _ix ^a _tu ^d _r ^d _e ^ed _wa ^a _s ^nd _co ^th _o ^e _le ^m _d ^ix _a ^t _n ^u _d ^re _d ^w _ilu ^a _t ^s _ed ^sti _w ^rre _ith ^{d u} _e ⁿ _th ^d _y ^e _l ^r _a ⁿ _c ^it _e ^ro _ta ^g _t ^e _e ⁿ _{. T} ^g _h ^a _e ^s r_{esdanic layer was washed with water, dried, filtered and the solvent was removed under uinugce ddic phrloersosmureet.ha Tnhee a rensdid mueeth waansol p ausrifi eeldue bnyts fl (agsrhad cieonlutm enlut ciohnro fmroamtog 0r%aph toy 5 o%ver m seitlihcaa gel 0 Y The product fractions were collected and the solvent was removed under reduced p ssure.nol). 2 LCieMldS: 1 m.4e0th go odf 1 in:t MerHm+e =di 4a8te6, 2 R4T (8 re}

=_{3% 0.8)53 min Preparation of intermediate 25} ^-128-

^{2 in-tNeirtmroebdeinazteene 2s4ulfon (1y.l40 chlo gri,d}

^{2 (.08877 g 34l)6, pyil) ddd portionwise to a solution of 5 ( wdaimse stthiryreladm ainto ro)poymrid teinmep (e1r7a mg, 0.14 mmol) in dichlodriometh (2a5n6e (8 µ.6l,4 m 2l.)8.8 The m rmeaocl)tion a mndixtu 4re- was washed with a 1N aquetouures h foyrd 3ro hcohulorrsi.c D aiccihdlo sroolmuteiotnh.an Tehe w oarsga andidce lday aenrd w tahse d orrigeadn,i fci layer} a_{nd the solvent was removed under reduced pressure. The residue was pu} ^ltered 0 _{column chromatography over silica gel using dichloromethan rified by flash 1 ( wgarasd rieemnto evleudtio unnd freorm re 0d%uc teod 8 p%re methanol). The product fractions weer aen cdol mlecettehdan aonld a thse e sloulevenntst Yield: 1.486 g of intermediate ssure.}

L_{CMS method 1: MH+ = 671, R 2T5 ( =770%.93)6 min}

1_{5 Preparation of intermediate 26}

T ^{(1e.t4r8a6bu gty,la 2m.2m2o mnimumol) fl iunor tiedtera (h4y.d4r4}

^{g 444 l) ddd to a solution of intermediate 25} t _{weamsp setriarrteudre a fto rro 2o0m h toeumrsp.e Mraoturere te} ^{f (6.66 l). Th tion mixture was stirred at room} _{20 fotrrab 2u4ty hloaumrsm aonndium at f 6lu0o°Crid feor (14 e hqo.)ur wsa.s Th aedd meidxt aunred w thaes m diixlututerde} ^{w soitlhutio enth.y Tlh aece otragteani acnd lay wears whaesd d wriiethd, w fialtteerr -1}

e^{d a2n9}

a^{d- nd a th seatu soralvteednt a wqauseo ruesmo svoeddium bicarbonate pressure. The residue was purified by flash column chromatography o under reduced} h_{eptane and ethyl acetate as eluents (gradient elution from 0% t} ^{ver silica gel using} 5 _{p Yrioedldu:c 8t0 fr0actions were collected and the solvent was removed undero re 1d0u0c%ed e pthreylss aucreet.ate). The LCMS met mhogd o 1f: in MteHr+m =ed 5i5a7te, R 2T6 ( =650%.55)9 min}

P_{reparation of intermediate 27}

^{10 A a s soolluuttiioonn o off in dtieisromperodpiaytle a 26 (650}

^{g 117 l) i 2 thyltetrahydrofuran (20 ml/mmol) and added simultaneously anzodicarb ylt (1.16 g, 5.85 ol) in toluene (20 ml/mmol) were triphenylphosphine (1.53d dropwise over a period of 3 hours at 90°C to a solution of} 15 9 _re0

s_d°

i_nuC

g_ce fo

d_dr

i_{c p} 3

h_r0

l_oers m

o_sinutes. Th⁴e ^g r^,ea ⁵c^.8ti⁵on ^m m^mi^ox^lt⁾ur ⁱe^{n t} w^oa^lus^en c^eoo ⁽l⁷e⁵d ^m an^l/d^mm th^oe^l) s^.o ^Tlv^he^en ^mt w^ixa^tus^re re ^wm^ao^sve ^sd^tirr u^en^dde ^ar^t u _{mureet.ha Tnhee a rensdid mueeth waansol p ausrifi eeldue bnyts fl (agsrhad cieonlutm enlut ciohnro fmroamtog 0r%aph toy 7 o%ver m seitlihcaano gle).l T Yhieeld p:r 2o3d9uc mtg fra ocft iinotnesrm weedreia cteol 2le7ct (e3d and the solvent was removed under reduced pressure. 20 LCMS method 1: MH+ = 539, RT =80%.66)2 min Preparation of example N7} ^-130-

^{T adod aed so cluestioiunm o cfa inrbteornmaetedia (2te4127 m (g2,00}

^{0.74g 037l) d tlh)i ip NhNdlim (4e0th µyl,lf 0o.r4m4a mmmidoel) (.1 T.1h1e m rel)a wctere 5 mixture was stirred at room temperature for 2 hours. The solvent was removed under reducioedn p} _A ^r ₎ ^e _. ^s _T ^s _h ^{ure. The residue was purified by reversed phase column chromatography (HPLC method} Y_{ield:e product fractions were collected and the solvent was removed under reduced pressure. LCMS 6 m5e mthgo odf 2 e:x MamH+pl =e 3 N574, (50%)}

1_{0 RT = 1.873 min}

E _{Exxa 8}

P_reaml

p_mp

a_{pralee N}

t_{io Nn8 o mfa inyte brem perdeiaptaere 2d8 following general scheme 1.}

^{15 t (e2r.t9-9Bu gt,y 8l-.c7h9lo mromdioml)e athnydls tirliaentheyl (a1m.5i9ne g}

e^{action was stirred at room temperatu ( 1055 l) dded to a mixture of intermediate 3 r r3e.0 f5o l, 21.97 l) in dichloromethane (26.37 ml).The and tert-butyl-chlorodimethylsilane (0. r 5 hours. More triethylamine (0.30 ml, 2.197 mmol)} ₂₀ ^{was stirred at room temperature15 o9ve gr,n 1ig.0h55 m Tmol) were added and the reaction mixture} d _{soiclhvelonrtom weatsha rneem.o Tvheed o urngdaneric r leadyuecre wdas pr wesassuhre} ^t

e_d ^.

. _{w Thi} ^h _teh ^e _w ^re

r_east ^{action mixture was diluted with} i_{edru and brine, dried, filtered and the chrraodmieantotg erlauptihoyn o frvoemr s 0il%ica to ge 1l0 u%si)n.g T dhiech plororodmucetth rified by flash column (g farancetio annsd w 7Ne}

e_{re am w}

c_mas

o_{lo pu}

l_{encia in methanol as eluents r Yeimeldo:ve 3.d1 u4n gde orf i rnetdeurmceeddi par ted and the solvent was 25 tees 2s8ur (e7.9%)} ^{LCMS method 1: MH+ = 456, RT = 0.676 min -131-} P_{reparation of intermediate 29}

5 ^{t (e3r.t1-4Bu gt,ox 6y.9c1arb momnyoll) a,n trhimydertihdye (1.81}

^{g, 8.29 l) ddd to a mixture of intermediate 28 mg, 0.35 mmol) in tetrahydroflaumrainn (2 (1.248 l, 8.98 l) nd 4-(dimethylamino)pyridine (43 More tert-butoxycarbonyl anhydride (0.73 ml). The solution was stirred at 80°C for 2.5 hours. 10 0.07 mmol) and triethylamine (0.250 m3l62 mg, 1.658 mmol), 4-(dimethylamino)pyridine (9 mg, 8} _p ⁰ _re ^° _s ^C _su ^fo _re ^r _. ² _D ^ho _ic ^u _h ^r _l ^s _o ^. _ro ^T _m ^he _et ^r _h ^e _a ^a _n ^c _e ^tio _w ⁿ _a ^m _s ^ix _a ^t _d ^u _d ^re _ed ^{w, 1a.}

a^{s796 mmol) were added and the mixture was stirred at} n_d ^co _t ^o _h ^{led and the solvent was removed under reduced} b_{rrienses.ure T.he Th oerg raensiicdu leay weras wa psur difireiedd, by filt felaresdh ae}

c_{n o}

o_drg

l_{um thanic layer was extracted with water and p ne c shorlovmenatt was removed under reduced dichloromethane and methanol as eluents (gradient elution fromography over silica gel using 15 p Yrioedldu:c 3t. f4r7ac gtio onfs in wteermree cdoiallected and the solvent was removed und 0e %r re todu 1c0e %d p orfe msseutrhea.nol). The LCMS method 1: MH+ = 55te6, 2 R9T (9 =1% 0.8)55 min}

P_{reparation of intermediate 30}

^{20 Iynl)tpehrmeneodlia (t7e2029 mg (1,.34.002 g, mm 2.o5l2),}

1 ^{2-diyl)l 4hflylph3p(4hi45-25,t4’,t6ra’-mtrieisthoyplr-o1p,3y,l2b-idioxaborolan-2-} (_{i1x9tur meg o,f 01.2,45-d miomxaonl)e a anndd p wotaatsesriu (3m:1 p,h 7o.5sp6h matle) a trnibdas thice ( m1.i6x0tur ge, w 3a esq. d)e wgaesre} ^ph

s_{e d} ^e

d_is ⁿ

b_s ^y y_o ^l _lv ^(Xphos) m _{beudbb inlin ag} ^{n mitmroogl)en wa gsa asdd therdou agnhd t thhee m mixixttuurree. wa Tset sratkis -(1t3ri2p-henylphosphine)palladium(0) (116 mg, 0.10 fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboriorrleadn- u2n-ydl)eprh neintroolgen (2 g1a6s a mt 8g0,°C 0 o.9v0e6rnig mht. More 4- 5 dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl mol), 2- p mhmosopl)h wateere tri abdadsiecd (4 a8n0d m thge, 0 m.9 (Xphos) (36 mg, 0.075 mmol) potassium ixt euqre.) w anads t settirrarekdis( utrnipdheern nyiltprohgoesnph ginaes)p aatll 8a0d°ium(0) (35 mg, 0.03 reaction mixture was cooled and the solvent was remo C for 6 hours. The} a_{cetate and water were added and th} ^{ved under reduced pressure. Ethyl} T_{he combined organic layers were drieed a,q fiulteeoreuds a lanyder th wea ssol evxetnratc wteads t rweimceov weidth u entdheyrl acetate. 10 p hreepstsaunree. an Tdhe eth reylsi adcueeta wtea ass p euluriefinetds ( by flash column chromatography over silica ge reld uusciendg product fractions were collected and thegr saodlvieenntt e wluatsio rnem froomved 0 u %nd teor 5 r0ed %uc oefd e pthreysls aucreetate). The Yield: 1.23 g of intermediate 30 ( .}

L_{CMS method 1: MH+ = 586, RT8 =3% 0.)}

1_{5 983 min}

P_{reparation of intermediate 31}

T

2^{0 ae stroalubtuiotynla omfm inotneirumme fluoride (1M lti i tt hyd f 066 g, 2.52 mmol) was added to m soixlututiore diate 31 (1.23 g, 2.10 l) i tt hydrofuran (6.30 ml). The reaction n w ina tset sratihrryeddro afutra rono,m 66 te mmgp,e 0r.a2t5u2re m omveorln)ig what. More tetrabutylammonium fluoride (1M temperature for 2 hours. The so s added and mixture was stirred at room di} _q ^c _u ^h _e ^lo _o ^r _u ^o _s ^m _s ^e _o ^th _d ^a _iu ⁿ _m ^e _b ^w _ic ^a _a ^s _rb ^a _o ^d _n ^{d lvent was removed under reduced pressure and} a _a ^e _te ^d. _so ^T _lu ^h _t ^e _ion ^o _. ^r _T ^ga _h ⁿ _e ^ic _org ^la _a ^y _n ^e _ic ^r _l ^w _ay ^a _e ^s _{r w} ^w _a ^a _s ^sh _d ^e _r ^d _ied ^w _, ⁱ _f ^t _i ^h _lter ^w _e ^a _d ^te _a ^r _n ^{and a saturated} _{25 r oevmero svielidca u gnedle urs riendgu dciechdlo prressure. The residue was purified by flash columnd c thhreom soalvtoegnrta wpahsy mreetshsanol). The product fraocmtioenthsa wneer aen cdo mlleecttheadno aln ads th eelue snotlsve (ngtra wdaiesnt re emluotivoend fr uonmde 0r% re todu 1c0e% p d 30 YCieMlure.}

L _{dS: 7 m10et mhogd o 1f: in MteHr+m =ed 4i7a2te, R 3T1 ( =720%.64)0 min}

P_{reparation of intermediate 32} -133-

A ^{de sgoalsution of intermediate 31tr (680}

^{g 144 l) i 2 thylttrahydrofuran (20 ml/mmol) was azodicsaerdbox byylate bu (b8b6l0ing mg, ni 4.o3g2 m g th gh th it . A solution of diisopropyl 5 n ait proegrieond g oafs 4 t5hro muinguhte thse a mti 9xt0u°rCe. t Boom}

a^thol

d ^{s) in toluene (20 ml/mmol) was degassed by bubbling eogluatsiosns were added simultaneously and dropwise over mmol) in toluene (75 ml/mmol). The mixture wed solution of triphenylphosphine (1.133 g, 4.32} w_{as cooled and the solvent was removed und} ^a _e ^s _{r r} ^{stirred at 90°C for 1 hour. The reaction mixture} _{10 flash column chromatography over silica gel usieduced pressure. The residue was purified by (gradient elution from 0% to 5% methanol). The pnrogdu dcicth flroarcotmionesth waneere a cnodlle mcteetdha annodl t ahse e sloulevennts w t Yiaesld r:e 3m4oved under reduced pressure.}

L_{CMS m6et mhogd o 1f: in MteHr+m =ed 4i5a4te, R 3T2 ( =532%.66)0 min}

1_{5 Preparation of example N8}

A ^{ml m)i wxtausre s otif intermediate 31 (346}

^{g 076 l) d 4N hydrochloric acid in 1,4-dioxane (2.28 0 temperaturerr.e Ddie athty rlo eotmhe tre amnpde mrat f 4 h , t 50C fr 2 hours and overnight at room 2 t} _a ^e _m ^m _o ^p _u ^e _n ^r _t ^at _o ^u _f ^re _me ^fo _th ^r _a ³ _n ⁰ _ol ^m _a ⁱ _n ⁿ _d ^ut _d ^e _r ^s _ie ^. _d ^Th _u ^eeth

n_d ^sa

e^{onol (1 ml) were added and the mixture was srtirred at room} r^li _v ^d _ac ^w _u ^a _u ^s _m ^fi _a ^lte _t ^r ₆ ^e ₀ ^d _º ^, _C ^w _. ^a _T ^s _h ^h _e ^ed _pro ^w _d ^it _u ^h _c ^t

s_{a t} ^d _w ^ie _a ^th _s ^y _o ^l _b ^e _ta ^h _i ^e _ned ^an _a ^d _{s t} ^a _he ^sm _H ^a _C ^ll _{l Y LCielt}

M_{l.dS: 2 m25et mhogd o 2f: e MxaHm+p =le 35 N48, R (8T4% =)}

2_{5 2.098 min}

E _{Exxaammppllee N N99 may be prepared following general scheme 2. Preparation of intermediate 33} ^-134-

^{Ahyd mrioxxtuyrpeip oefrid 3i-nbero-1m-coa-5rb-cohxlyolarote-py (1ra.9}

^{9l g[1,59.89]pyi idli) i (2 d0y0 te gt,ra 8h.6y0 mmol) and tert-butyl 4- 5 s mtimrreodl) w atas ro aodmde tedm apnedra thtuere re faocrti 1on h mouixr.tu Sreod wiuams s htiyrdreridde at (6 ro0o%m in tem mpidnr}

e^eo

r^arfau

t^{ulran (25.80 ml) was r oeil, fo 310 mg, 12.90 sodium hydride (60% in mineral oil, 30%) was added and the reaction mixturer w 1a hso sutr. More room temperature for 1 hour. The reaction mixture was cooled to 0°C and a saturated aqirured at} _{10 ammonium chloride solution was added and the aqueous layer was extracted with ethyl ace} ^e _t ^ous T_{he solvent was removed under reduced pressure. The residue was purified by flash coluamten. c frhormom 0a %tog troap 3h0y % ov oefr e stihliycla a gceetla utes)in.g Th heep ptraondeuc atnd ethyl acetate as eluents (gradient elution re fractions were collected and the solvent was 15 Yimeldo:ve 82d6 un mdger of reduced pressure.}

L_{CMS method 1: in MteHr+m =ed 3i9a8te, R 3T3 ( =241%.12)5 min}

P_{reparation of Intermediate 34}

^{20 m Intermediate 33 (826 mg, 2.08 mmol)}

^{di l d i 4N hyd}

r^{el a hanol (6.24} a^m).

l_t ^{o T}

a^vh

n^ee

d^{d m}

w ^t _a ^wi

s^ixct

u^eur

s ^{uen w}

e_d ^d _w ^ea

i^rs

t_h ^{r s}

o^et

u^dir

t^ure

f^cd

u^e _r ^{d a}

t_he ^{ptr reososmure t. Tphe ctompo fund 4 w hoausrs o.ro}

b^{t Tc}

a^oh

i^nlulo

e^er

d^nic

a^{e a}

s ^wci

t^had

e^{s in met}

h^{ydddreodch twloircice a acnid} Y _s ^d C_{ieMldS: 6 m78et mhogd o 2f r purification in the next step.}

L _{: in MteHr+m =ed 2i9a8te, R 3T4 ( =980%.30)}

2_{5 6 min}

P_{reparation of Intermediate 35} -135-

S ^{inotedrimumed tiaritaece 3t4ox (y1b.o0r5o4hy gd,ri 3d.e1 (1}

^{339 g 632 l) ddd portionwise to a solution of mg, 4,74 mmol) and triethylam6ine (1.3l)1,82 m-[tl, 9t-.b48ty ml(mdiol)thyl)ilyl]oxyacetaldehyde (90%, 830 5 m sal)tu arantded me atqhuaenoouls (4 s modl).iu Tmhe b riceaarcbtioonnat meix sture was stirred in at a r mooixmtu treem opfe 1r,a2t-udriech folorro 2e hthoaunrse. ( A9} e_{xtracted wit} ^{olution was added and the aqueous layer was} r_{emoved undher d riecdhulocreodme ptrheasnsuer.e T.h Teh organic layer was dried, filtered and the solvent was over silica gel using dichloromethane aend re msideuthean woals as pu erliufieed by flash column chromatography 10 methanol). The product fractions were collected and the sonltvsen (gtr wadaisen rte emluotvioend f uronmde 0r%}

p _{red touc 3e%d Yr}

L_Ciees

M_lds

S_{:u 1re}

m_.2.

e_{3t3ho gd o 1f: in MteHr+m =ed 4i5a6te, R 3T5 ( =860%.72)5 min}

1_{5 Preparation of intermediate 36}

A ^{thr mouixgthur tehe of m 1ix,4tu-dreio.x Ianntee}

^{d t (31120 l) dg d by bubbling nitrogen gas acid (0.42 g, 2.70 mmorl), tedtiratkis 3(5trip (8h1e8nylpgh,os 1p.8h0in l), (5- ino-2-fluoro-phenyl)boronic 20 d pihc}

t^oy

8^sc

5^plo

°^hh

C^aet _f ^exy

o_r ^tlrpi ₁ ^bh

6^aoss

h^ipch

o_u ⁽ⁱ¹ⁿ

r_s ^.o1- .⁴²

T^6’,4

h ^g’,

e^,6

r ^3’-t

e_a ^eri

c^qis

t^.o

i^)p

o_n ^wreo

m^rpeyl

i_x ^ab

t_u ^dip

r^dh

e^eedny

w_a ^al

s^{n (dX}

c_o ^tphhe o^eo)p l ^msa)lla

i^{x (t3d}

u^3iu

r^{e mm}

w^g(

a^{,0) (46 mg, 0.04 mmol), 2- s 0. s0ti7rre mdm uonl)de arn ndit proogtaesnsi guam} a ^s o_{rganic layer was w ed and diluted with ethyl acetate. The reduced pressure. Thaesh reesdid wueith w wasate pru,rif dierided b,y filtered and the solvent was removed under 25 u Tshieng pr doidcuhclotr foramcetitohnasne we arned co mlleetchteadno aln ads th eelu seonlvts fl}

e_{n (ags}

t_rh

w_{aad c silica gel sieo}

r_nlu

e_tm

m _en

o_{luvt c}

e_ioh

d_nro

u_{n fmratography over}

d_{oemr r 0e%duc toed 5 p%re msseutrhea.nol).} ^{Yield: 731 mg of inteHr+m =e -136- LCMS method 1: M d 4i8a6te, R 3T6 ( =840%.87)7 min}

P_{reparation of intermediate 37}

5 ^{2 in-tNeirtmroebdeinazteene 3s6ulfo (n7y3l1 chl}

^{gid, ( 10.5410 g 18l1), pyild)i (1d3d4d µ pl,rtio 1n.wise to a solution of (dimethylamino)pyridine (10 mg, 0.08 mmol) 51 mmol) and 4- 10 was sti in dichloromheathnaen wea (4s.5 a3dd meld). a Tnhde th reea octrigoann micix latuyree w r} a_n ^a _d ^{s w} _th ^ar

e^srehd

s^e _o ^{d at}

l_v ^{w r}

e_n ^iot _t ^hom

w ^a _a ^{1 te}

s^Nm

r ^ap

e^qe

m^ura

o^et

v^oue

e^ur

d^{s h fo}

u^yr

n^{d 3}

d^r _e ^{o h}

r^{cohurs. Dichloromet}

r_e ^lo _d ^r _u ^ic _ce ^a _d ^cid _p ^s _re ^o _s ^lu _s ^t _u ^io _re ⁿ _. ^{. T} _T ^h _h ^e _e ^{organic layer was dried, filtered} c_{olumn chromatography over s residue was purified by flash (gara ilica gel using dichloromethane and methanol as eluents wsd rieemnto evleudtio unnd freorm re 0d%uc teod 5% methanol). The product fractions were collected and the solvent 15 Y LCieMldS: 7 m46et mhogd o 1f: in MteHr+m =ed 6i7a1te p}

, _{R 3re 4r}

T_{7s (s}

=_7u

1_%e.

._{03)9 min}

P_{reparation of intermediate 38}

^{Tetrabutylammonium fluoride (1.33 g, 1.33 -137- (7 mmol) was added to a solution of intermediate 37 tem46pe mragt,ur 1.11 mmol) in tetrahydrofuran (3.33 ml). The reaction mixture was stirred at room 5 and a satureat feodr a 4q8u heoours. The mixture was diluted with ethyl acetate and washed with water t} _c ^h _h ^e _ro ^s _m ^o _a ^lv _t ^e _o ⁿ _g ^t _ra ^w _p ^a _h ^s _y ^r _o ^e _v ^m _e ^o _r ^vu

s^es

i^{d s}

l_ic ^uo

a^{nddium bicarbonate solution. The organic layer was dried, filtered and} g^e _e ^r _l ^r _u ^e _s ^d _i ^{uced pressure. The residue was purified by flash column} e_{lution from 0% to 10% methanol). Tnghe d picrohdlourcotm fethane and methanol as eluents (gradient remov ractions were collected and the solvent was Yield:e 36d2 un mdger of re indtuecrmed pressure.}

1_{0 LCMS method 1: MH+ =ed 5i5a7te, R 3T8 ( =590%.64)8 min}

P_{reparation of intermediate 39}

^{15 a A solution of i}

a^{d sdoeldutio snim oufn}

l^{ta dt}

n^ieiesrom

o^pe

u^rsod

l^ypiayt

a^le

n ^{a 3}

d^{z8o dd (287 g 052 l) i 2 thyltetrahydrofuran (20 ml/mmol) and ricoaprwbiseyl otver (0 a.52 pe g, 2.60 ol) in toluene (20 ml/mmol) were triphenylphosphine (682 mg, 2.60 mmol) in toluenreiod (75 of m 2l/m hmouorls at 90°C to a solution of 9} _e ⁰ _d ^° _u ^C _ce ^fo _d ^r _p ³ _r ⁰ _es ^m _su ⁱⁿ _re ^u _. ^te _T ^s _h ^. _e ^Th _re ^e _si ^r _d ^e _u ^a _e ^cti _w ^on _as ^m _p ^ix _u ^t _r ^u _if ^r _ie ^e _d ^w _b ^a _y ^s _f ^c _la ^o _s ^o _h ^le _c ^d _o ^a _lu ⁿ _m ^d _n ^th _c ^e)

h_r ^s.

o^{o T}

m^lvh

a^ee

t_o ^{n m}

g^t _r ^wix

a_p ^atu

h^sre

y ^{re was stirred at} r _o ^m _ve ^o _r ^ve _s ^d _ilic ^under _{20 u ascientgate d)i.ch Tlohreom preotdhuacnte fr aancdtio entshy wle arceet caotelle acsted elu aenndts th (egra sodliveenntt e wluatison re fmroomve 0d% un tode 5r0 r%a edu ect ghe eyl dl p Yriessure. 5 LCeMldS: 1 m41et mhogd o 1f: in MteHr+m =ed 5i3a9te, R 3T9 ( =502%.33)}

2 _{7 min}

P_{reparation of example N9} -138-

T ^{adod aed so cluestioiunm o cfa inrbtermediate 39 (14}

^{1 g 026 l) i NNdimethylformamide (0.78 ml) were mixture was stirredo anta rtoeo (m16 t9em mpge,r 0a.t5u2re for 5l) d thiph l (30 µl, 0.31 mmol). The reaction 5 p Ar}

h^)e.s

e ^Ts

p^hu

r^ere

o_d ^p.

u^{ro T}

c^dh

t _w ^{uec r}

a^te

s ^fsr _d ^aid

r^cu

i_e ^tie

d^{on w}

u^sa

n_d ^ws

e^{e p}

r^rueri

v_a ^cfi

c^oe

u^ldl _u ^e _m ^{c btye} _a ^{d re avnedrs tehd ho}

e ^pu

s^hr

o^as

l^vs.

e^{e Th}

n^{t ceo wlu s}

a^mol

s ^rnve

e^{m cnht was removed under reduced orvoemda utongdrearp rheyd (uHcPedLC pr mesestuhroed} T ^. Y_{ield: t 60°C for 16 hours.}

L_{CM 18mg of example N9 (20%)}

1_{0 S method 2: MH+ = 354, RT = 1.977 min}

E _Exammple

i_{llxuastraptlee N}

d _N1

f_o10

r_{0 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N2 g.e Tnheera plr socdhuecmt wea 1s a onbdtai ancecdo ardsin thge to HC thle sa plrt.ocedures}

^{15 Ex} _x ^a _a ^m _m ^p _p ^l _l ^e _e ^N1

E _N1 ¹ _{1 may be prepared following general scheme 1 and starting from example N8.}

^{A mixture of example N8 (133 mg, 0.38 mmo -l)1 a3n9d- 4.18 mmo sodium hydride (60% in mineral oil, 100 mg, atmospherel) fo inr 1 a hnohuyrd.ro Ious N,N-dimethylformamide (1.14 ml) was stirred under nitrogen 5 was stirred at room tempderoamtuerteha foner 2 (2 h7o µl, 0.44 mmol) was added and the reaction mixture e rexmtraocvteedd u wnidther d riecdhulocreodme ptrheasnsuer.e T.h Tehe or rgeau}

s^inrs

d^{iuc. W}

e ^{la wya}

a^ete

s^rr

p ^{w w}

u^aa

r^ss

i^{fie d added and the aqueous layer was drie bdy, f flialtsehred and the solvent was over silica gel using dichloromethane and methanol as eluents (gradien cto elulumtn chromatography methanol). The product fractions were collected and the solvent was removioend f uronmde 0r% red to 5% 10 pressue. uced} L ^{Yield: 1r05 mg of example N11 (75%)}

E_{CxaMmSp mlee Nth1o1d ( 21: MH} ⁺ _{= 368, RT = 2.107 min}

a_{cid in 1,4-diox0a5ne mg (0,.08.729 m mmol) was dissolved in dichloromethane (2 ml).4N hydrochloric temperature for 5 hours. Diethl)yl w eathser ad adnedd m aentd the reaction mixture was stirred at room 15 s ati srrmeadll a atm roooumnt te omf mpeertahtaunreol. fo Trh 3e0 c mominpuoteusn.d T wheas shoa}

d_ln

r_idol

i_{ed w (a1}

u_{s m}

n_{d fiellt)e were added and the mixture was rr veadc,u wuamshed with diethyl ether and o at 60ºC. The product was Ybitained as the HCl salt.}

L_{CeMldS: 8 m7e mthgo odf 2 e:x MamH+pl =e 3 N611 (82%)}

2_{0 8, RT = 2.114 min}

E _Ex

i_llxa

u_ample

s_{mtraptlee N}

d _N1

f_o12

r_{2 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N8 g.e Tnheera plr socdhuecmt wea 1s a onbdtai ancecdo ardsin thge to HC thle sa plrt.ocedures}

^{25 E}

E^xxamp

P_re ^a _p ^m _a ^pl

r_a ^{lee N3}

t_io ^N1

n¹³ _of ^m _in ^a _te ^y _r ^b _m ^e _e ^p _d ^r _ia ^e _t ^p _e ^a ₄ ^re ₀ ^{d following general scheme 2.} -140-

S ^{proodpiuamne- h1y,3d-rdidioel ( (620.3%37 in m ml,i 3neral oi}

^{l 170 g 710 l) as added at 0°C to a solution of mixture was stirred at room te2m.2p5eraturle) i for 30h mydinutes t. Tthehy mdirofuran (19.35 ml). The reaction 5 b reroamctioo-n5- mchixloturore-p wyarasz sotliorr[1e,d5- aat] rpoyorimmi tdeimnepe (1r.50 g, 6.45 mmol) wxtausre a wddaesd co inol oende to po 0r°tCion a.nd Th 3e- ml) w ature for 10 minutes. Dry N,N-dimethylformamide (2} T_{he r} ^a _e ^s _a ^a _c ^d _tio ^d _n ^ed _m ^an _ix ^d _tu ^t _r ^h _e ^{e r} _w ^e _a ^a _s ^ctio _p ⁿ _ou ^m _re ^ix _d ^tur _in ^{e was stirred at room temperature for 2 hours.}

a_{queous layer was extracted with dichlotorom ae 5th0a%ne. a Tqhueeo cuosmb aimnemoniumchloride solution. The 10 w wiaths s burisnpee,n ddreiedd, in fi eltethryeld a acnetdat tehe (5 s molvl)e,n thte w salsu removed under reddu ocrgeadn picre lasyseurrse. w Tehree w reassihdeude ceooled to room temperature. The solid was filterrryed w,a wsa hsehaetded wi atht 6 e0th°Cyl f aocre 1ta0te m ainnudte dsrie adnd un thdeen r r Yideuldc:e 1d.2 p5ressure.}

1_{5 LCMS meth go odf 1 in:t MerHm+e =di 2a7te3, 4 R0T (7 =1% 0.5)39 min}

P_{reparation of intermediate 41}

^{20 i Intermediate 4}

a^{nticm a}

h^on

l^osh

r^py

o^hd

m^ero

e^reus

t^{h aan d0 ndic (h4 e alo.0 (2 sr4 0loum g mrrlye,t 1 ) w oh4}

f^{a. a mn8e5 se at (}

d^h4

d^{y5 l) elsdu dlfl)o.}

r^{on Td pyh tithy wl misee.th Tantli i}

e^{sulfoi (}

n^t3097

a^{te (2.8sl,}

5 ^{c 2}

g^o2

,^{o.28 mmol) were dissolved 1le6d.3 t4o m 0°mCol u)n inde arn nhiytrdorgoeun d s} m_inutes ^{he reaction mixture was stirred for at 0°C for 15} d_{ichlorom aenthdan aet a rnodom the te omrgpaenraictu lraeye fror 3 hours. The reaction mixture was diluted with 25 f fiultrethreedr p aunrdifi tchaetio sonlv uent was removed und wears re wduacsehded pr wesitshu breri.n Teh.e T choem oproguanndic w laayse urs wedas w ditrhieodu,t LCMS method 2: MHse+d = i 3n5 t1h,e R nTex =t 0 st.7ep0.1 min} ^-141- P_{reparation of intermediate 42}

5 ^{I cn}

N^at

,^Nrebr

-^om

d^ne

i^madteeiat

t^{h (e}

y^{2l. (7}

f³⁴

o⁵¹

r^{m3a gm,.24}

i^d20

e^{.2 m}

(^{6 mm}

m^mo)

l^ol

/^{ml,) (S)}

m^old(

)^{. p)}

T^ht2py

e ^{rei li}

a^{ctio ididid (1th.597l g (,795.602 m mgm,o 7l).4 w0er mem suosl)p,en sdoeddium in (S)-(+)-2-pyrrolidinemethanol (1 n mixture was stirred at 60ºC for 4 hours. More added and the reacti 0%), sodium carbonate (10%) and potassium iodide (10%) were} 0 _c ^{aqueous layer wason mixture was stirred at 60ºC for 2 hours. Water was added and th} e^ee _{1 po d armembined organic lay} ^e _e ^x _r ^tr _s ^ac _w ^te _e ^d _re ^w _d ^it _r ^h _ied ^a _{, f} ^m _ilt ⁱ _e ^x _r ^tu _e ^r _d ^e _a ^o _n ^f _d ^d _t ⁱ _h ^ch _e ^lo _s ^r _o ^o _l ^m _ve ^e _n ^th _t ^a _w ⁿ _a ^e _s ^a _r ⁿ _e ^d _mo ^m _v ^e _e ^t _d ^ha _u ⁿ _n ^o _d ^l _e ⁽ _r ^9: _r ¹ _e ⁾ _d ^. _u ^T _c ^h m_{ssounreia. s Tohlueti roensi adnude m weatsha pnuorlifi aesd e bluye fnlatssh (g craodluiemnnt e clhurtoiomna frtoogmra 0p%hy to ov 5e%r s aimlica gel using 7N The product fractions were co 4llected and the solvent was remov monia solution). 15 Yield: 1.53 g ed under reduced pressure.}

L_{CMS metho odf 2 in:t MerHm+e =di 3a5te6, R2T (5 =8% 1.6)01 min}

P_{reparation of intermediate 43}

^{20 t (e}

r^1r

e^.t

a^5- c^3Bu

t_io ^gt

n^{,yl 4-c}

w^. _a ^3h

s^1lo

s ^mro

t_ir ^mdi

r_e ^om

d^l)et

a ^ah

t^ny

r^dls

o_o ^tilra

m^{iente (078 g 517 l) dldd to a mixture of intermediate 42} t^h _e ^y _m ^l _per ⁱ _atur ⁽ _e ^1. _f ⁰ _o ⁹ _{r 4} ^g, _h ¹ _o ⁰ _u ^. _r ⁷ _s ⁷ _{. More t} ⁾ _e ⁱ _rt-b ^d _u ^ic _ty ^h _l ^l-^o _c ^r _h ^o _l ^m _or ^e _o ^t _d ^h _i ^a _m ⁿ _e ^e _th ⁽ _y ¹ _l ² _s ^. _i ⁹ _la ³ _ne ^m ₍ ^l) ₂ ^. ₀ ^T _% ^he ₎ ^{a hnodurs tr.ie Tthhyelam reiancetio (2n0% m)ix wtuerree w adadsed di and the -1 m42ix-ture was stirred at room temperature for 1,5 washed with water and brine. The orgalunteicd la wyeitrh w daisch dlroierodm, feiltthearende a anndd th tehe so olrganic layer was} 5 ^{under reduced pressure. The residue was purifie vent was removed} g _{meelth uasninogl). d Tihcehlo prroom} ^{d by flash column chromatography over silica} d_{uecthta frnaectio annsd w meereth caonlolelct aesd e alnuden thtse s (gorlavednietn wta elution from 0% to 10% pressur s removed under reduced Y LCieMldS: 1e}

m_.8.

e_{1th go odf 1 in:t MerHm+e =di 4a7te0, 4 R3 (89%)}

1_{0 T = 0.707 min}

P_{reparation of intermediate 44}

A ^{thr mouixgthur tehe o mf 1ix,t4u-rdeio.x Inatneerm aenddiat}

^{4t3 ( (13.716 g 1,1325 l) dg sed by bubbling nitrogen gas 15 ( d0ic.7y0clo gh,ex 4yl.p5h0os mphminool)-,2’, t4e’t,r6a’k-tirsii(stroipphroepnyyllbp .}

i^{hpohsep7h5ine)palll)a,d (5iu-m(0i)o- (21-7fl4uor mog-p,he 0n.1y5l)bo mromnoicl), ac 2id- p 8h0o°Csph oavetern trigibhat.si Mc ( nyl (Xphos) (181 mg, 0.38 mmol) and potassium o2r.e38 (5 g-,a 3m einqo.-)2 w-felureor aod-pdheedn aynl)dbo throen miixture was stirred under nitrogen gas at 2’,4’,6’-triisopropylbiphenyl (Xphos) (30%), potassicum acid ph (3o0s%ph)a,te 2-di tcryibcaloshicexy (l3p0h%os)phi annod- 20 t} _u ^e

r_n ^tr _d ^a _e ^k _r ^is _n ⁽ _i ^t _t ^r _r ⁱ _o ^p _g ^h _e ^e _n ^ny _g ^lp _a ^h _s ^o _a ^s _t ^p ₈ ^h ₀ ⁱⁿ _° ^e _C ^{)palladium(0) (30%) were added and the reaction mixture was stirred} w_{eimthov weadte ur.nd Tehre re adquuceeodus pr le f}

a_so

y_sr

e_{u 4}

r_{re h}

w_.o

a _Tu

s_hres.

e_{x rte T}

r_ash

c_ideea

t_{u r}

e_{ed wcatison di mluitxetdur weit wha dsic choloolreodm aenthda tnhee a snodlve wnats wheads}

_{25 layers were dried, f with dichloroemethane. The combined organic w maestha pnuorilfi aesd e bluyen flail}

t_sstehre

(_{gr cd}

a_{odl aun}

i_emd

n_{n th}

t _{e ce}

l_{hr soomlvaetnotg wraapshy rem ovoevred si ulicnad gre reld uusciendg p driecshslourroem. Tethhean reesid auned coiellledc:t ution from 0% to 8% methanol). The product fractions were Y 1e.d3 and the solvent was removed under reduced pressure. 0 LCMS me6th go odf 1 in:t MerHm+e =di 5a0te0, 4 R4T (7 =3% 0.8)}

3 _{89 min Preparation of intermediate 45} ^-143-

^{2 (1-N.3i6tro gb,e 2n.7z2en memsuolfl)on aynld c phylorirdidi}

^{(0 (2686 g 299 l) ddd t a solution of intermediate 44 5 m origxatunriec la wyaesr w satirred at room temp6er µalt,u 3re.54 overnigl)h it. d Diichhlloromeththaannee (8 w.1a6s m ald).d Tehde a renadct tiohen extracted with dsic whalosrhoemde wthitahn ae.1N Th aequ ceoomubsin heyddro ocrghalonriicc a lacyider ssolu wteiorne. T dhrieed a,qu feous layer was} s_{olvent was removed under reduced pressure. The residue was} ^{iltered and the} 0 _{chromatography over silica gel using dichloromet purified by flash column 1 e relumtioovne fdro umnd 0e%r re todu 1c0% methanol). The product frahcatinones a wnedre m ceotlhleacntoeld a asnd el tuheen stsolv (gernatd wieanst Yield: 1.65 g of intermeedd pressure.}

L_{CMS method 1: MH+ =i 6a8te5, 4 R5T (8 =9% 1.0)20 min}

1_{5 Preparation of intermediate 46}

T ^{(1e.t6r5ab gu,ty 2la.4m1m monmiuoml) f inluo teritdreah (}

^{y076 g 289 l) ddd t solution of intermediate 45} 0 _{t memixtpuerera wtuares f sotirrr 3ed ho autr 8s0.° MCo froer t} ^d

3_etra ^{f (7.23 l). Th ti mixture was stirred at room} _{2 hobuurtsy.la Tmhem monixiutumre flu woarsid ceo (o3le0d% a)n wdas th aed sdoelvde anntd w tahse r reemaoctvioedn} ^{u anndde ar s readtuurcaetedd p areqsuseuorues. T shoedi ruemsid buicear wbaosna dties -s1}

s^o4

o^{l4vlue- tdion in. d Tihcehl oorrgomaneicth laanyeer a wndas w darsiehde,d fi wlteitrhed wa atner the solvent was removed under reduced pressure d} 5 ^{chroma . The residue was purified by flash column} e _relumtioovn ^t

e _f ^o

d_ro ^g

u_m ^rap

n_{d 0} ^{hy over silica gel using dichloromethane and methanol as eluents (gradient} Y _{e%r re todu 10% methanol). The product fractions were collected and the solvent was LCieMldS: 9 m55et mhogd o 1f: in Mtec}

H_r+med

=_{ed p}

5_ir

7_ae

1_tses

, _{R 4u}

T_{6re (.}

=_{690%.64)6 min}

1_{0 Preparation of intermediate 47}

A ^{de sgoalsustieodn of by inte brmubebdliinagte 4 n6itr (o9g1e5n}

^{g g 160 th glh) i 2 thyltetrahydrofuran (20 ml/mmol) was 5 azodicarbox th iture. A solution of diisopropyl 1 n ait proegrieond g oafsy}

3 ^tla

h^ht

o^{reouu (}

r^sg9h50

a^{t th mg, 4.80 mmol) in toluene (20 ml/mmol) was degassed by bubbling 9e0 mixture. Both solutions were added simultaneously and dropwise over} i_{n toluene (75 ml/mmol).} ^° _T ^C _he ^{to a degassed solution of triphenylphosphine (1.259 g, 4.80 mmol)} c_{ooled and the solvent was rem moixvteudre was stirred at 90°C for 1 hour. The reaction mixture was 20 column chromatography over silica g uenlder redu hced pressure. The residue was purified by flash e colullteiocnt t fhreom pro 2d0u%ct t fora 8c0ti%ons e.th Tyhle a scoeltvaetnet) u}

w _as

a_nin

s_{dg dicehplotaroneme atnhdan eet/heytlhy alce actaetteat aes (1 e:l1u)en wtsas (g ursaeddien tot LCMS method 1: MH+ = 553, RT = 0.712 min removed under reduced pressure. Preparation of example N13} -145-

T ^{ceos aium sol cuation of intermediate 42 (1}

^{60 l) i NNdi thylformamide (4.80 ml) were added mixture warsbo sntiarrteed (1 a.t0 r4o3 g, 3.20 l) d thiph l (200 µl, 1.92 mmol). The reaction 5 w laayser asd wdeedre a dnrdie tdh,e fi altqeureedooum}

a^{s tem}

n ^{layeprer waatusre ex otrvaecrtneidgh wt.it Ah d 1iNchl aoqroumeoeuthsa snoed.iu Tmhe h cyodmrobxinideed s oorlguatinoinc was purified by flash columdn th cehr solvent was removed under reduced pressure. The residue methanol as eluents (gradient elutioomatography over silica gel using dichloromethane and collected and the solvent was removend f urnodm 0% to 8% methanol). The product fractions were 10 Y} _LC ^ie _M ^ld _S ^{: 3} _m ⁵⁸ _et ^m _ho ^g _d ^o ₂ ^f _: ^{example N13 (61%) er reduced pressure.} E _MH ⁺ _{= 368, RT = 2.064 min}

(_{4x:a1m, 6ple N13 (358 mg, 0.97 mmol) was dissolved in a mixture of dichloromethane/methanol was st.i25 ml).4N hydrochloric acid in 1,4-dioxane (50 µl) was added and the reaction mixture 15 s ature for 30 minutes. Diethyl ether was added and the mixture was utnir}

e_dred

l_{edr: 3 v arr room temper}

a_{ted at 1c r}

4_{uoom temperature for 30 minutes. The solid was filtered and the compound was dried Yi mumg o aft e 6x0aºmCp foler N 1613 ho (8u8rs. The product was obtained as the HCl salt.}

L_{CMS method 2: MH+ = 368, RT =% 1).987 min}

2_{0 E Ex}

i_llxample

u_am

s_{traptlee N}

d _N1

f_o14

r_{4 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N8 g.e Tnheera plr socdhuecmt wea 1s a onbdtai ancecdo ardsin thge to HC thle sa plrt.ocedures}

₂₅ ^E _E ^x _x ^a _a ^m _m ^p _p ^l _l ^e _e ^N _N ¹ ₁ ⁵ _{5 may be prepared follo}

_{ig g l h 1.} ³ _ca ^-b _n ^ro _b ^m _e ^o _p-_r ^N _ep ^-[ _a ¹ _r-_e ^[2 _d ^-[

t _a ^te

e_c ^r

r_mc ^t _o ^-b

e_rdd ^u

i_i ^t

a_n ^y

t_g ^l(d

e _{t 4o} ^im

8 _t ^e _h ^t _e ^hy _m ^l) _e ^s _t ⁱ _h ^ly _o ^l] _d ^o _s ^{xye -th1y4l6]--4-piperidyl]pyrazolo[1,5-a]pyrimidin-5-amine} P_{reparation of in described to obtain intermediate 5.}

5 ^{A piperid myl]ixptyurraezol of inter}

^{dit 3b N[1[2[t tbutyl(dimethyl)silyl]oxyethyl]-4- mineral oil, 790o m[1g,,53-a3]p mymrimoli)di in-5 a-nhydirou (s1 N.5,N g, 3.30 l) nd sodium hydride (60% in nitrogen atmosphere for 1 hour. Iodomethane (23-d7im µel,th 3y.8lf0or mmmamide (9.9 ml) was stirred under mixture was stirred at room temperature for 2 hours. Water wasol a)d wdaesd a adndded th aen adq tuhe reaction 10 was extracted with dichloromethane. The organic layer was dried, filtered and the soelovuesnt la wyaesr} r _oe

g_vm

r_earov

d_{ie seinldi e}

t_{ca und}

e_{lu gtier}

o_{l r}

n _ue

f_{sduced pressure. The residue was purified by flash column chromatography ( roinmg 07%N to am 5m%o anmiam soonluiatio in in methanol and dichloromethane as eluents 15 an n methanol). The product fractions were collected Y LCied}

M_{ld the solvent was removed under reduced pressure.}

S_{: 1 m.0e0th go odf 2 in:t MerHm+e =di 4a6te9, 4 R8T (6 =5% 0.7)06 min}

P_{reparation of intermediate 49}

^{20 A thr mouixgthur tehe of m 1ix,t4u-rdeio.x Inatneerm}

^d

i^{oxaborolan-2-yl)phenol (0.d61it g, 4t82.5 ( (13}

6^.01

m^{0m g 6,3}

o ^{29 l) dg d by bubbling nitrogen gas d l).,13 tetrakisl(),t 4-fl -3-(4,4,5,5-tetramethyl-1,3,2-} m_{g, 0.09 mmol), 2-dicyclohexylphosphino-2’,4’,6’-triisopro} ^ri _p ^p _y ^{henylphosphine)palladium(0) (104} 5 _{m unmdoelr) n aintrdog peontas gsaisum at p 8h0o°sCph oavteer tnriibgahst.ic T (h1e.3 r6ea gc,t 3io enq m.)i wxteurrel}

e _ab

w_dip

a_dh

s_eedn

c_{o ay}

o_nl

l_{d (X}

e_{d thpeho}

a_{n ms}

d_{i)x (100 mg, 0.21 2 thtuere s wolavesn sttir wreads} ^{w removed under reduced pressure. The resid -u1e47 w-as diluted with dichloromethane and washed laiythers wa wter. The aqueous layer was extracted with dichloromethane. The combined organic} 5 ^{was pureifrieed dried, filtered and the solvent was removed under reduced pressure. The residue} m _{coelltehcatneodl a ansd e} ^b

t_hlu ^y

e_{e sn} ^fla

o_ts ^sh

l_{ve (g} ^{column chromatography over silica gel using dichloromethane and} n_{rta wdaient elution from 0% to 5% methanol). The product fractions were Yield: 786 mg o s remo4v%ed under reduced pressure.}

L_{CMS method 1f: in MteHr+m =ed 5i0a0te, R 4T9 ( =70.86)6 min}

1_{0 Preparation of intermediate 50}

T ^{(7e8tr6ab mugty,la 1m.5m7o mnimumol) fl iunor tiedtera (h0yd}

⁴⁹

e^{mperature overnight. More tetrabuf g 18}

t^{ylam (8}

m^{4.o7n1 l)}

i^{uml). flu Toh ddd}

r^{ide (10ti to}

%^{n a}

) ^{w m s}

a^ixo

s^tluu

a^rt

d^eion

d ^{weda osf in}

a^{n sdttierrr}

t^{em hded e ai retate 49 t a rcotoiom 15 m}

s ^{pariexture was stirred at room temperature for 2 hours. The solvent was removed under reducend} s_o ^{tusrsautreed. a Tqhueeo ruesidue was dissolved in dichloromethane and washed with water and a} c_{hlrvoemnatto wgarsap rheymo} ^s

o_v ^s

v_e ^o

e_d ^{dium bicarbonate solution. The organic layer was dried, filtered and the} _{20 r s uilnicdaer g reelduced pressure. The residue was purified by flash column e relumtioovned fro umnd 0e%r re tdou 8c% methanol) u.s Tinhge d pircohdlourcotm freatchtaionne}

s_{ure. s a wnedre m ceotlhleacnteodl a asnd el tuheen stsolv (gernatd wieanst}

_{L YCieMldS: 4 m50 ed pres}

e_{t mhogd o 1f: in MteHr+m =ed 3i8a6te, R 5T0 ( =740%.44)5 min}

2_{5 Preparation of intermediate 51}

^{P dryyrid diicnhelo (2ro3m0 µl, 2.85 mmol) was added to a s -1o4lu8t-ion of intermediate 50 (365 mg, 0.95 mmol) in 2.85 mmol). Tehthea rneeac (1tio0n m ml/mixtmuroel). The mixture was cooled to 0°C and thionyl chloride (210 µl,} 5 ^{for 2,5 hours. The mixture was d wiluatsed sti wrriethd d atic rholoormom teemperature for 1 hour and under reflux} s _{saotlvuerantte wda asqu reemouosve sdod uinudmer b riceadrubcoendat pere ssoslution. The org} ^t _a ^h _n ^a _i ⁿ _c ^e _la ^a _y ⁿ _e ^d _{r w} ^w _a ^a _s ^sh _d ^e _r ^d _ied ^w _, ^it _f ^h _ilte ^w _re ^a _d ^ter _an ^a _d ^nd _th ^a _{e further p ure. The compound was used in the next step with LCMS muertihfiocadti 1o:n M.H+ = 404, RT = 0.549 min}

1_{0 Preparation of example N15}

I ^{dnrtoeprmwiesdeia atte 9501ºC (0 o.v9e5r a mm peorli)od w oafs 2}

^{d hi l td i NNpdiith oyflfo cremsiaummicdaerb (o3n2at mel) (1 a.5n5d g a,d 4d.e7d 15 mmol) in N,N-dimethylfo}

n ^{wea.s T choeolermamide (63 ml). The reaction mixture was stirred at 90 ºC for 1 hour5 T . dihcehlo mroixmtuerteha codm abninded wa otregran wicas lay aedrdsed w. The aqueous layer was extracted with filtered and the solvent was removed under reducede prrees wsuarseh.e Tdhe w riethsid wuaeter and brine, dried, colu} _d ^m _i ^{n chromatography over silic was purified by flas} s_gra ^{a gel usin} _{fractions were collected and th} ^th e^s _{20 (} ^{g dichloromethane and methanol as eluen} p_ohlavseenetn

c_{o wt}

l_{ua e}

m_slut

n _rieo

c_mn

h_{o f}

r_ovro

m_{emdat u 0}

o_n%

g_{drae t}

p_ro

h _{rye 1d0% methanol). The product}

(_{HuPceLdC p mreesthsoudre A.) T.h Te product was further purified by reversed solvent was he product fractions were collected and the YCieMldS: 9 m6e mthg re}

o _om

d_{f 1 eo}

:_xv

M_aemd

H_{+p ul =end Ne1r5 re (d2u7c%e)d pressure. 25 L 368, RT = 2.073 min}

E _Exa

i_llxuampl

s_mtraptle

e_{e N}

d _N1

f_o16

r_{6 th mea pyr be prepared following general scheme 1 and according to the procedures Preparation of intermepeadriaattieon 52 of example N2.} -149-

A

s^{ti mrreixdtu aret r oofo imnte termmepdeiraatetu 1re0 f (o0r.922 hoursl) andd a 4tN 50 hyCd forh 2l hiourcsi.d E inth 1yl,4 a-cdeiotaxatene an (2.76 ml) was 5 added. The two layers were separated and the organic layer was washed w d brine were o} _re ^rg _si ^a _d ⁿ _u ⁱ _e ^c _w ^la _a ^y _s ^er _pu ^w _r ^a _ifi ^s _ed ^dr _b ^ie _y ^d _f ^, _la ^f _s ^il _h ^te _c ^re _o ^d _lum ^an _n ^d _ch ^th _r ^e _om ^s _a ^o _t ^l _o ^ve _g ⁿ _ra ^t _p ^w _h ^a _y ^s _ov ^re _e ^m _r ^{oved under reducedi pthre wssauterer.. T Thhee} m_{ethanol as eluents (gradient elution from silica gel using dichloromethane and collected and the solvent was remo 0% to 10% methanol). The product fractions were 10 Yield: 243 m ved under reduced pressure.}

L_{CMS methogd o 1f: in MteHr+m =ed 5i3a8te, R 5T2 ( =491%.17)4 min}

P_{reparation of intermediate 53}

^{15 I mnt}

w^al)e

s^{.r Sm}

s^toe

i^rdd

rⁱⁱ

e^ua

d^mte

a ^{h 5}

t^y2

r^{odor (imd2e23}

t^{e (6 m 4}

m^0p%g,

e^{r ian 0.}

t^{u m1}

r^{ien foll)il, 30 dgi, 0.l82d i l)hydro audsde Nd,N an-ddim theeth reylafocrtimonam miidxetur (e2} r_{eadcetido.n Th meix ttwuroe la wyas stirred at ro} ^r _om ^{1 h} _t ^o _e ^u _m ^r. _p ^I _e ^o _r ^d _a ^o _tu ^m _re ^eth _fo ^a _r ⁿ ₂ ^{e (} _h ² _o ⁹ _u ^µ _rs ^l, _. ⁰ _E ^.4 _th ⁷ _y ^m _{l a} ^m _c ^o _e ^l _t ⁾ _a ^w _te ^as _an ^a _d ^dd _w ^e _a ^d _te ^a _r ^nd _we ^th _r ^e a_{d e w charsom rae ers were separated and the organic layer was dried, filtered and the solvent 20 tmogorvaepdhy u onvdeerr si rleicdauc geedl u psriensgsu driec.hlo Trohmeet rheasnideue and wa mseth paunriofield as b eylue flnatssh (g croalduimennt} ^{e relumtioovne fdro umnd 0% to 10% methanol). The prod -1u5c0t- fractions were collected and the solvent was} Y_{ield: 106 mg} ^er _of ^{reduced pressure.}

L_{CMS method 1 intermediate 53 (47%)}

5 _{: MH+ = 552, RT = 1.204 min}

P_{reparation of example N16}

A ^{mixture of intermediate 53 (106}

^{g, 0.19 l) d i rbonate (12}

1^{0 N,N-dimethylformamide (2.0 ml) was stirred for 2 minut 4 g, 0.38 mmol) in a wd th}

h^ad

e^tee

s^rd

o ^{w a}

l^ven

e^rd

n^{et a wde}

a^{dse reda}

r^e.c

m ^Ttiho

o^en

v^{e tdw moixt ed m s un lau}

d^yre

e^{err wsa}

r^{e ws}

d^{eur s es. Thiophenol (20 µl, 0.23 mmol) wa cetir}

e^{d sre ppra a}

e^rsat

s^{t reo}

u^do

r^{e a.n Td tem}

h^{e thpeea}

r^{e or}

s^ridgtu

u^ar

t^{hromatography over silica gel using dichlorom eneic o}

w ^lv

a^ae

s^yren

p^rig

u ^wh

r^ifat.

i^{es E}

d ^dtrh

b^iey

y^dl

f^{, a la fc}

s^{ilethetar cete od a lu an mndd c n} _{15 elution from 0% to 30% ethy} ^{ethane and} _w ^e _e ^th _r ^y _e ^l _c ^a _o ^c _ll ^e _e ^t _c ^a _t ^t _e ^e _d ^a _a ^s _nd ^el _t ^u _h ^e _e ⁿ _s ^ts _ol ⁽ _v ^g _e ^r _n ^a _t ^d _w ^ie _a ⁿ _s ^t r _Ye

L_{Cimeoved under reduced presls aucreet.ate). The product fractions MldS: 2 m9e mthgo odf 2 e:x MamH+pl =e 3 N6176, R (4T2% =) 2.047 min 20 E Examl}

i_llxuasmp

t_{raptle N}

e_{ed N1}

f_o17

r_{7 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N8 g.e Tnheera plr socdhuecmt wea 1s a onbdtai ancecdo ardsin thge to HC thle sa plrt.ocedures}

^{Example N -151- E} _ex ^x _a ^a _m ^m _p ^p _l ^l _e ^e _N ^N1

1¹⁸

7⁸ _. ⁱ _T ^s _h ^o _e ^b _p ^ta _ro ⁱⁿ _d ^e _u ^d _ct ^a _w ^s _a ^a _s ^s _o ^id _b ^e _ta ^-p _in ^r _e ^o _d ^du _a ^c _s ^t _t ^d _h ^u _e ^ri _H ⁿ _C ^g _l ^th _sa ^e _lt ^M _. ^{itsunobu reaction in the preparation of}

⁵

E ^{Ex le}

a_c ^xamp

c^a _o ^m _rd ^p _i ^l _n ^{e N}

g ^N1

t_o ¹⁹⁹ _th ^m _e ^a _p ^y _ro ^b _c ^{e prepared following general scheme 1 and starting} _io ^f _n ^ro _o ^m

a_{eindeudre ass o thfe th HeC lals sta tlwt.o steps d f e} ^e _x ^x _a ^a _m ^m _p ^p _l ^l _e ^e _N ^N ₁ ¹ ₁ ⁷ T_{he product was obt escribed in the preparat .}

¹⁰

E ^Exxa

P_re ^am

p^mp

a^pl

r_a ^{lee N}

t_io ^N2

n²⁰

o⁰ _f ^m _in ^a _te ^y _r ^b _m ^e _e ^p _d ^r _ia ^e _t ^p _e ^a ₅ ^re ₄ ^{d following general scheme 1.}

15

^{tdeiortx-Boiustoyilndo (3liSn-)2-3-y-(l)heytdhryolx mymetehtahnyel)spuiplfeornaaztiene (- - 311}

.^-5

7^c2

4^{a-r gb,o 1x3yl.a8t8e mm (2o.0l), s go,diu 9m.2 c5arb momol), 2-(1,3- 27.75 mmol) and potassium iodide (1.997 g, 12.03 mmol) was stirred at 70ºC onvaete (2.941 g, 5 reaction mixture was cooled and the solvent was removed under reducedrn pigrehst.s Turhee D .} T_h ^ic _e ^hl _s ^o _o ^ro _lv ^m _en ^e _t ^th _o ^a _f ⁿ _t ^e _he ^wa _fi ^s _ltr ^a _a ^d _te ^de _w ^d _a ^t _s ^o _r ^t _e ^h _m ^e _o ^r _v ^e _e ^s _d ^idu _u ^e _nd ^a _e ⁿ _r ^d _re ^th _d ^e _uc ^m _e ⁱ _d ^xtu _p ^r _r ^e _es ^w _s ^a _u ^s _re ^f _. ^ilt _T ^e _h ^re _e ^d _re ^o _s ^v _i ^e _d ^r _u ^a _e ^p _w ^a _a ^t _s ^{h o} _p ^f _ur ^C _if ^e _ie ^li _d ^te _b ^®. f_{lash column chromatography over silica gel using dichloromethane and methanol as eluenty (gradient elution from 0% to 5% methanol). The product fractions were collected and the sol s 10 was removed under vent Y LCie reduced pressure.}

M_{ldS: 2 m.8e gth oofd in 1t:e MrmHe+d =ia 3te905,4 R (T78 =% 1).314 min}

P_{reparation of intermediate 55}

^{15 A eth mainxotulre (4 o5f i mntle)rm waesdia hteea 5te4d (3 a.5t06 g0,}

^{C 8.99 ighl)t. Tdh hyd tiinoe (64%, 860 mg, 13.48 mmol) in suspension was filtered to remove the white solid. The solvent onf mixture was cooled and the} _{20 reduced pressure and the residue was dissolvedn in ethyl acet} ^{the filtrate was removed under} w _anit

u_dh

r_{ifi t a}

c_hn

a_{e a}

t_{io sq}

n_oulve

i_neonu

t_hts

e _{w 1}

n_aM

e_{s s}

x_{t reoum}

s_mdi

t_{eopv.ed hy udnrodxeirde re sdoulcuetidon pr aesdsu brrein.e T.h Tehe pr oa}

o_rt

d_ge

u_a.

c_{n T}

t_iche

w _{laa o}

s_yreg

u_ra

s _wn

e_{daics l}

w _{da itryr hieeodu, w}

t _{f fia ults reh trhee edd p r Preparation of intermediate 56} -153-

T

a^{coe ato mniitxritluere (2 o7f. i0n9ter mmle)d wiaates 5 a5d (d2e.3d43 g-,b 9ro.0m3o-5-chll)oro-dpy triazthoylol[ ine (5.076 ml, 36.12 mmol) in 5 mmol). The reaction mixture was stirred at 80 1,5-a]pyrimidine (2.10 g, 9.03 a} _co ⁿ _l ^d _um ^th _n ^e _c ^s _h ^o _ro ^lv _m ^e _a ⁿ _t ^t _og ^w _r ^a _a ^s _p ^{removed under reduce°dC p froers 2su hroeu.r Ts.he Th rees reidaucetio wna msix ptuurriefie wdas by co folalesdh} p_{roduc hy over silica gel using dichloromethane and methanol as eluents. The Yield: 2t. f0r7a7cti gon osf i wnteerrem ceodlliaectete 5d6 a (n5d1 the solvent was removed under reduced pressure. 10 LCMS method 1: MH+ = 456, RT = 1%.00)5 min}

P_{reparation of intermediate 57}

A ^{mm moixl)tu arend of tr iinettehrymlaemdiiantee ( 58624 (2}

^{µ.0l,775 g, 4.56 l), t tbtylhl dimethylsilane (760 mg, 5.02 15 t} _w ^e

h_e ^m _re ^pera _a ^t _d ^u _d ^r _e ^{e for 18 hours. More tert-.b9u3tyl-chlol)ro idim diethhlylsilaneth (0.6 e (1q5.) a mnl)d w triaesth sytliarrmedine at (2 ro eoqm.)} c_{lloverondtim weatshdy rls a}

e_imlan

o_nd

v_{ee ( th}

d_{0e.1 un e m}

d_qe.ix)t

r _wur

r_eae

d_{su a w}

c_da

e_ds

d_{ed s}

p_{r at}

e_nir

s_dre

s_{u td}

r_{hee a}

. _mt

T_{hixet ruoro}

c_em

o_{m wa f}

p_sor

o_{u s}

p _{ntidr 4re wd h}

a _ao

s_{tur rs}

u_o.

s_{oem M}

d _{fo r worre ith 1o h te}

u_{otut-rb.u Tthyle- so}

L_{uCrMifiSca mtioenth iond th 1e: M neHx+t s =te 5p7. further 20 0, RT = 1.537 min} ^-154- P_{reparation of intermediate 58}

5 ^{A t}

t^{reim m yr}

t^raeix

h^thtu

y^dle

r^{aom o}

f^uif

r^{n i}

a^ente

n ^{( (1rm}

3^.09e0d

m^1ia

l^{) mte}

w^{la, 5}

s ^{173 s. (}

t^{64 t}

i^r8.56

r^{ed at 6l)l),}

5^{°Cd for 4t-b}

4^{(d hit y}

o^{urtsh.y Mlb}

o^reiyl

t^e)rpn

t^-yh

b^{riyddinriede (5 (61.2 m6g, m 0l,.456.4 m7m moml)ol i)n, eq.) and 4-(dimethylamino)pyridine (0.1 eq.) were added utoxycarbonyl anhydride (1.2 ethyl acetate was added and the organic layer was extr . The reaction mixture was cooled,} d_{ried, filtered and the solvent was removed under} ^{acted with water. The organic layer was} _{10 f plar io cnh ch}

i_os

e_dh

l_{du c}

:_co

2_tl

. _fu

6_r3am

6_{cnt g osro}

f _{i wm}

n_tea

e_rreto

m _cg

e_ora

d_lliaep

t_{etye 5d ov}

8 _ae

(_nr

8_{d silica gel using re hdeupcetan peres asnudre e.th Tyhle a rceestiadtuee a wsa eslu peunritfsie.d Th bey Y 6% th)e solvent was removed under reduced pressure.}

L_{CMS method 1: MH+ = 670, RT = 1.778 min}

1_{5 Preparation of intermediate 59}

A ^{the mix mtuixretu oref.1, I4n-tdeiromxaendeia atend 5}

^{8t ( (31, 24 l) dg d by bbbling nitrogen gas through dioxaborolan-2-yl)phenol (1. 2.636 g, 3.94 l), 4-fl -3-(4,4,5,5-tetramethyl-1,3,2-} _{20 0 a.08 mmol), 2-dicyclohexylp} ¹ _h ³ _os ^g _p ^, _h ⁴ _in ^.7 _o ³ _-2 ^m _’,4 ^m _’,6 ^o _’ ^l-⁾ _t ^, _ri ^t _i ^e _s ^t _o ^r _p ^a _r ^k _o ^is _p ⁽ _y ^tr _lb ^ip _ip ^h _h ^e _e ⁿ _n ^yl _y ^p _l ^h ₍ ^o _X ^s _p ^p _h ^h _o ⁱⁿ _s ^e ₎ ⁾ ₍ ^p ₁ ^a ₅ ^l ₃ ^lad _m ^iu _g ^m _{, 0} ⁽⁰ _.3 ⁾ ₂ ⁽⁹ _m ³ _m ^m _o ^g _l) ^, n_{nitrdog peonta gsassiu amt 8 p5h°oCsp ohveartenig thritb.a Tshice r (e3ac etqio.)n w meixretur aed wdeads c aonodled th.e Et mhyilxt aucreeta wteas an sdti wrreadter u wndeerer} ^{a wdadsed re amndov theed tw uond laeyrers re wdeurceed sep parreastseudr.e T.h -1e5}

T^{h o5}

e^{r-ga rneicsid lauyeer w waass dr pieudri,fie fildtere bd and the solvent chromatography over silica gel using dichloromethane and ethyl a y flash column} e_{lution from 0 % to 30 % of ethyl acetate). The product f} ^{cetate as eluents (gradient} 5 _{w ractions were collected and the solvent Yias removed under reduced pressure.}

L_{CeMldS: 2 m.2e3t2ho gd o 2f: in MteHr+m =ed 7i0a1te, R 5T9 ( =813%.79)4 min}

P_{reparation of intermediate 60}

^{10 T ae stroalubtuiotynla omfm inotneirummed fluiaoterid 5e9}

^{(1 d}

i^{xture was stirred at room tem (M2p.e2r3a2lt}

t^{ur gi}

e^{, f 3 i}

o^{.r128 tt hy}

h^{oursl.) T if}

h^{e t mt, 4}

i^{xth.y7d7fl,ra 4n.77 (2 m0m mol)l). w Tahse a rdedaecdtio to m n and washed with a saturated aqueous sodium bica ure was diluted with ethyl acetate 15 w} _pu ^a

l_ur ^s

e_ifnie ^die

t_d ^r

s _b ^d

(_gy ^,

r_{a fl} ^f

d_a ^ilt

i_s ^e

e_h ^re

n_{t c} ^d _{o ellu} ^a

u_m ^nd

t_{ionn c} ^{the solvent was removedrb uonndaetre r seodluuctieodn a pnreds bsruinree.. T Thhee o rergsaidnuice la wyaesr} e _{fhroromma 0to %gr taoph 1y0 o %ve orf s miliceath gaenlo ul)s.in Tghe di pchrolodruocmte frtahcatnioen asn wde mreet choalnleoclte ads Y an}

L_Cied

M_{ld th}

S_{:e 1 m. s7o}

e_7le

t_4v

h_{o gn}

d _{ot e}

1_{f w}

: _ina

M_{tse r}

H_r+mmv

=_{eod 5i8aed under reduced pressure.}

2_{0 7te, R 6T0 ( =951%.43)0 min}

P_{reparation of intermediate 61}

^{A de sgoalsustieodn of by inte brmubebdliinagte 6 n0itr (o1g0e0n mg g,a 0s.17 th m - rom15}

u^o6

g^{lh)- in th 2e-me mthixytluteretr.ah Aydro sfoulruatnion (20 o mfl/m dimisol) was azodicarboxylate (170 mg, 0.85 mmol) in toluene (20 ml/mmol) was degassed by bopropyl nitrogen gas through the mixture. Both solutions were added simultaneously an ubbling 5 a} _in ^p _to ^e _l ^r _u ^io _e ^d _ne ^of ₍₇ ⁴ ₅ ^h _m ^ou _l/ ^r _m ^s _m ^at _o ¹ _l) ¹ _. ⁰ _T ^° _h ^C _e ^t _m ^o _i ^a _xt ^d _u ^e _re ^ga _w ^s _a ^s _s ^ed _st ^s _ir ^o _re ^lu _d ^tio _a ⁿ _{t 1} ^o ₁ ^f ₀ ^tr _° ⁱ _C ^ph _f ^e _o ⁿ _r ^y ₁ ^lp _h ^h _o ^o _u ^s _r ^{phine (223d m dgr,o 0p.w85ise m omvoelr)} c_{ooled and the solvent was removed under reduced pressure. Th . The reaction mixture was column chromatography over silica gel using heptane and e residue was purified by flash fractions were collected and the solvent was rem ethyl acetate as eluents. The product 10 Y LCieMldS: 2 m7e mthgo odf oved under reduced pressure.}

2 _{in:t MerHm+e =di 5a6te9, 6 R1T (2 =8% 5.1)91 min}

P_{reparation of example N20}

^{15 A}

m^{rl m}

i^{)ed wixatu}

u^sre

n^{d set oirrfr ve in}

a^dte

c^{u ar}

u^tm

m ^roe

.^od

T^miate

h^{e te 3}

p^m1

r^{opde (6}

u^ra1

c^{tt0u wreg}

a^{s f,o 1}

o^{r.207 hours.l) Dietdhy 4lN wa hsyd ardodcehdlo,ri tche ac siodli idn w 1,a4s-d fiilotexraende a (1nd0 d LCMS method 2: MH+ = 3 btained as the HCl salt.}

2₀ ^{69, RT = 1.987 min}

E _{Exm e N}

i_llxa

u_asmp

t_rapl

t_{leed N2}

f_o21

r_{1 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N7 g.e Tnheera plr socdhuecmt wea 1s a onbdtai ancecdo ardsin thge to HC thle sa plrt.ocedures}

_{25 Example N22}

^E _ill ^x _u ^a _s ^m _tra ^p _t ^l _e ^e _d ^N _fo ² _r ² _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^fo _a ^l _m ^low _pl ⁱ _e ^ng _N8 ^g _. ^{e -} Tⁿ¹

h^e5

e^r7a- p^l _r ^s _o ^c _d ^h _u ^e _c ^m _{t w} ^e _a ¹ _s ^a _o ⁿ _b ^d _tai ^a _n ^c _e ^c _d ^o _a ^rd _s ⁱⁿ _th ^g _e ^to _HC ^th _l ^e _sa ^p _l ^r _t. ^ocedures

^Ex

5 _Ex ^a _a ^m _m ^p _p ^l _l ^e _e ^N _N ² ₂ ³ _{3 may be prepared following general scheme 1 and starting from example N20.}

A ^{trie mthixytluarmein oef e (2x3ample N20 (230 mg}

^{057 l) f ldhyde (37%, 50 mg, 1.14 mmol) and 10 stirred at room t8 µl, 1.71 mmol) i it f dihl bthne and methanol (4:1, 5 ml) was a addddeedd. a Tnhde r tehaecet oimorgnpe}

a ^mra

n^iicxtuture

l^{are fo}

y^{e wr}

r^{a 1}

w^{s h}

a ^sstoirurr

e^e.

x^{d S}

t^{ra ao}

c^td

t ^rium

e^{odom tr}

w^{i ti}

t^eace

h^{m aptoex}

s^{raytuorero fhoyrd 3rid heou (2rs4.2 D micgh,lo 1r.o1m4e mthmaonle) w waass solution. The organic layer was dri aturated aqueous sodium bicarbonate} p_{ressure. The resi} ^{ed, filtered and the solvent was removed under reduced} 5 _{h reemptane and ethyl adcueetat wea ass p eulureifinetds. b Tyhe fl parsohdu ccotlu frmacntio cnhsro wmearteog corallpehcyted ov aenr silica gel using 1 YieMldo}

S_{:ve 1 und}

m_{3d9et mhoger}

d _{o 2f re}

: _ed

M_{xuac d the solvent was Hme}

+_{pd pressure.}

L_{C =le 38 N32,3 R (T64 =% 2).061 min 20 E Exxaammppllee N N2244 may be prepared following general scheme 1 and starting from example N23.} -158-

E ^{Sxoadmiupmle h Nyd2r3id (e63 (6 m0%g, i 0n.1 m6in memraoll}

^{)il, 40 dig,l 1.6d0 i hl)yd a Ndd,Ned-di amnedth thylefo rremaamide (1 ml). 5 was stirred at room temperature for 1 hour. Iodomethane ction mixture r seaatucrtiaotned m aixmtumreon wiuams s cthirlroerdide at s rooloum (11 µl, 0.18 mmol) was added and the tion tem wepreera atudrdeed fo.r T 2he ho twuros. la Eytehrysl a wceerteate se apnadra atend a aqnudeo thus organic layer was dried, filtered and the solvent was removed under r e residue was purified by flash column chromatogra educed pressure. The} _{10 methanol as eluents (gr} ^{phy over silica gel using dichloromethane and} c _{Yoiell adient elution from 0% to 10% methanol). The product fractions were ledc:t 4ed and the solvent was removed under reduced pressure.}

L_{CMS m4e mthgo odf 2 e:x MamH+pl =e 3 N9274, R (6T9% =) 2.127 min 15 E Example N2}

u_asxia

l_nm

t_{.gp thle 25}

e _{N pro5ce mdauyre b aepp plrieepda froerd th foello pwreinpgara gteionner oafl N sc1h1e.m Thee 1 p arondduc stta wrtainsg o fbrtoamine edxa amsp thlee N H2C2 s l}

^{20 E}

E^x _x ^a _a ^m _m ^p _p ^l _l ^e _e ^N _N ² ₂ ⁶ _{6 may be prepared following general scheme 1 and starting from example N8.} -159-

1 ^{su-Csphelonrsoipoynrrolidine-2,5-dione (50}

^{g, 0.34 l) dded in one portion to a stirred stirred for at o rfo eoxmam tepmlep Ner8at (u1r00 mg, 0.28 l) i hl f (3 ml). The reaction mixture was 5 d biicchalrobroonmaeteth saonleutio ann.d Th mee athqae}

u^{neo fo}

o^lr

u^{s 955 hours. The reaction mixture was diluted with a mixture of la:5yer a wndas w eaxsthed with an aqueous saturated sodium organic layers were dried, filtered and the solventracted with dichloromethane. The combined residue was purified by flash column chromatograp whays o rvemoved under reduced pressure. The 10 acetate as eluents (gradient elution from 0% to 20%er e stihliycal a gcel using heptane and ethyl d} _p ⁱ _r ^c _o ^h _d ^l _u ^o _c ^ro _t ^m _fr ^e _a ^t _c ^h _t ^a _io ⁿ _n ^e _s ^a _w ⁿ _e ^d _re ^m _c ^e _o ^t _l ^h _le ^a _c ⁿ _t ^o _e ^l _d ^a _a ^s _nd ^elu _th ^e _e ^nt _s ^s _o ⁽ _lv ^g _e ^ra _n ^d _t ^ie _w ⁿ _a ^t _s ^e _r ^l _e ^u _m ^tio _o ⁿ _ve ^f _d ^rom _und ^0e

e^%tat

r _r ^te

e^o)

d_u ^{6 f}

c^{%ollowed by using} e_d ^m _p ^e _r ^{thanol). The} r_{esidue was further purified by reversed phase column chromatography (HPLC metehsosdure. The prod ruct fractions were collected and th we. A). The 15 T Th e solvent was removed under reduced pressuras added prhe}

e_{ess me}

u_is

r_{xidue was dissolved in dichloromethane and 4N hydrochloric acid in methanol etu.re was concentrated, ethanol was added and the solvent was removed under reduced Yield: The product was obtained as the HCl salt.}

L_{CMS 2 m7e mthgo odf 2 e:x MamH+pl =e 3 N8286, R (2T5% =) 2.250 min}

2_{0 E Exa}

i_llxuample

s_{mtraptlee N}

d _N2

f_o27

r_{7 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N8 g.eneral scheme 1 and according to the procedures Preparation of intermediate 62} -160-

A ^{12. m16ixture of [(3S,8aR)-1,2,3,4,6,7,8,8}

^{thyd py l[1,2-a]pyrazin-3-yl]methanol (1.9 g, dichlorom memthoal)ne an (d36.428-(1 m,3l-)dio wxaosisoidli-2-yl) tldhyde (2.76 g, 14.59 mmol) in 5 t rroiaocmet toexmybpoerroahtuyrderi fdoer 1 (56.1 h5o4ur gs,. D 24ic.h32 st}

l^{or mirr}

o^mmed

e^{otlh) a}

a ^wt

n^{aes roo}

w ^am

a^{d temperature for 1.5 hours. Sodium sd aeddd.e Tdh,e th reaction mixture was stirred at of a saturated aqueous sodium bicarbonate solution was addede d mroipxtwuirsee, w fas stirred and 5 ml water. The two layers were separated and aqueous layer was extracted withol dloicwhelodro bmye 5 ml of} _{10 The combined organic layers were dried, fil} ^thane. p _dr

o_{ice tered and the solvent was removed under reduced 5hs}

%_lsourore

7_m.

N_{e T}

a_{tmhhae residue was purified by flash column chromatography over silica gel using t mnoen aiand so alu 7tiNon a immonia solution in methanol as eluents (gradient elution from 0% was removed under reduced pnre msestuhraenol). The product fractions were collected and the solvent 15 Yield: 3.52 g of 2 in:t MerHm+e .}

L_{CMS method =di 3a3te0, 6 R2T (8 =8% 1.5)47 min}

P_{reparation of intermediate 63}

^{20 m A}

^{l, 26.40 rem m}

m^oix

o^lv)tu

e ^ir

d^{ne of intermediate 62 (2.90 g, 8.80 l) d hydrazine (50/60% in water, 850 µ u entdhearn roeld (u5c1ed m pl)re wssausre st airnrded t t p ture for 16 hours. The solvent was} w_{as suspended in a mixture of ethyl} ^t _a ^h _c ^e _et ^r _a ^e _t ^s _e ^id _a ^u _n ^e _d ^{was co-evaporated with toluene. The residue} w_{aosdhuecdt w waitsh u estheydl w acitehtoautet. fu Trhthee sro pluverinficta otfio thne in fil tthraete m}

n_{e we}

x_at

t_{shanol (95/5), filtered and the solid was pr st reepm.oved under reduced pressure. The 25} ^T _pr ^h _e ^e _pa ^s _r ^u _a ^b _ti ^s _o ^e _n ^q _o ^u _f ^e _N ^nt _8. ^{steps to obtain example N -12671- are based on the procedures used for the}

^{5 E}

E^{x pl}

e_x ^xam

a^a _m ^m _p ^p _l ^le

e^{e N}

N ^N2

2²⁸

0⁸ _. ⁱ _T ^s _h ^o _e ^b _p ^ta _ro ⁱⁿ _d ^e _u ^d _ct ^a _w ^s _a ^a _s ^s _o ^id _b ^e _ta ^-p _in ^r _e ^o _d ^du _a ^c _s ^t _t ^d _h ^u _e ^ri _H ⁿ _C ^g _l ^th _sa ^e _lt ^M _. ^{itsunobu reaction in the preparation of}

1^{0 E Exa pple}

a_c ^x _c ^am

o^m _rdi ^l _n ^{e N29}

g ^N _to ²⁹ _the ^m _p ^a _r ^y _oc ^b _e ^e _d ^p _u ^r _r ^e _e ^p _s ^a _il ^r _lu ^ed _str ^f _a ^o _t ^l _e ^lo _d ^w _f ⁱ _o ⁿ _r ^g _th ^g _e ^en _p ^e _re ^ra _p ^l _ar ^s _a ^c _t ^h _io ^e _n ^m _o ^e _{f e} ¹ _x ^, _a ^s _m ^ta _p ^r _l ^t _e ⁱⁿ _N ^g ₁ ^f ₁ ^ro _. ^{m example N27 and}

^Example

1₅ ^E _ill ^x _u ^a _s ^m _tra ^p _t ^l _e ^{e N}

d ^N3

f_o ³⁰

r⁰ _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^f _a ^l _m ^l _pl ⁱ _e ^g _N8 ^g _. ^{l h 1 and according to the procedures} _{Preparation of intermediate 64} ^-162-

^{[ a(n3dR, t8eartR-b)-u1ty,2l, N3,-4(2,6-o,7x,o8e,8thay-ol)cctaarhbyadmroapt}

^{y (36l6[12g,] 2p.y30i 3ly)l] imne dthanol (300 mg, 1.92 mmol) 5 s wtairsred ad adte rdo.o Tmhe tem repaecrtaiotunre m fixotru 1re.5 w haosur sst.ir Sreoddi autm ro troiamce tteomxypb ichloromethane (5.76 ml) was eorarotuhydride (814 mg, 3.84 mmol) triacetoxyborohydride (814 mg, 3.84 mmol) was added and the rearecti for 1 hour. More sodium room temperature for 15 hours. A saturated aqueous sodium bicarboonna mixture was stirred at} _{10 till pH 7 and the aqueous layer was extracted with u a mixture of dichlorom} ^{te solution was added} ( _{c9o:m1)b.in Tehde a snodlve pnutrif oiefd b boyth fl laasyher csol wuamsn r cehmroomveadtognradpehry re odvuecre sdilic pare gsesulr uee}

s_.th

i_{n Ta}

g_{hnee r aensiddu meesth waenroel and methanol as eluents (gradient elution from 0% to 20% methanol). The p driochloromethane were collected and the solvent duct fractions Yield: 40 was removed under reduced pressure.}

1_{5 LCMS m9et mhogd o 1f: in MteHr+m =ed 3i0a0te, R 6T4 ( =710%.30)4 min}

P_{reparation of intermediate 65}

^{20 Idn}

T^ihote

e^xram

p^ne

r^{oediate 64 (409 mg, 1.37 mmol) ti d i a 4N hydrochloric acid solution in 1,4- d autct ro woams u tesmedpe wriathtuoruet f fourrth 2e hro puurif.ic Tahtion inl thet nexts s rteemp.oved under reduced pressure.} T _{prheepa froalltoiownin ogf N s8te.p Tshe to pro odbutacitn wa esxa ombtpaliene Nd3 a0s t ahree H bCals seadlt. on the procedures used for the} -163-

E^xa

E^xample

i_llus ^m _tra ^p _t ^l _e ^{e N}

d ^N3

f_o ³¹

r¹ _th ^m _e ^a _p ^y _re ^b _p ^e _a ^{prepared following general scheme 1 and according to the procedures} 5 _{ration of example N18 and N11.}

E

E^x _x ^a _a ^m _m ^p _p ^l _l ^e _e ^N _N ³ ₃ ² _{2 may be prepared following general scheme 1 and starting from example N20.}

^{10 N m,mNo,Nl′,N′-Tetramethyl-O-(1H-benzotri}

^{l1yl) i h afluorophosphate (167 mg, 0.44 mmol)) a wnads N a,dNded to a mixture of e pl N20 (80 g, 0.20 mmol), acetic acid (10 µl, 0.22} r_e ^{pylethylamine (245 µl}

e_adcut ^-diisopro _r ^{, 1.40 mmol) in dimethylformamide (0.60 ml). The} _{15 r cioend m prixetsusruere wa asnd sti threed r aetsi rdouoem w teamsp peurraiftiuerde f boyr 2 re hveorusresd. T phheas seolv ceonlutm wnas c rhermomovaetodg uranpdheyr} ^{r (HPLC method A). The product fractions we -r1e64 c-ollected and the solvent was removed under Yeu}

L^CideMldc

S^{:e 1d}

m^{7 p s}

e ^mre

t^hgs

o ^ou

d^fr

2 ^ee

:^x.

M^{amH+pl =e 4 N32 (21%)}

5 ^{11, RT = 2.345 min} E _Exammple

i_{llxuastraptlee N}

d _N3

f_o33

r_{3 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N8 g.e Tnheera plr socdhuecmt wea 1s a onbdtai ancecdo ardsin thge to HC thle sa plrt.ocedures}

^{10 E Example N}

a_c ^x _c ^a _o ^m _rd ^p _i ^l _n ^e _g ^N3

t_o ³⁴⁴ _th ^m _e ^a _p ^y _ro ^{be prepared foll ig g l h 1, starting from example N33 and} o_{btained as the HCl scaeldt.ures illustrated for the preparation of example N11. The product was}

^{15 E Ex p}

i_ll ^xa

u^am

s^m _tra ^pl

t^le

e^{e N}

d ^N3

f_o ³⁵

r⁵ _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^fo _a ^l _m ^lo _pl ⁱ _e ^g _N2 ^g _{0. The} ^l _pro ^h _{duct w} ¹ _as ^an _o ^d _bta ^a _i ^c _n ^c _e ^o _d ^rd _a ⁱⁿ _s ^g _th ^t _e ^o _H ^th _C ^e _{l s} ^p _a ^r _l ^o _t. ^cedures

E_{xample N36}

^E _ac ^x _c ^a _o ^m _rd ^p _i ^l _n ^e _g ^N _to ³⁶ _the ^m _p ^a _r ^y _oc ^b _e ^e _d ^p _u ^r _r ^e _e ^p _s ^a _il ^r _lu ^ed _str ^f _a ^o _t ^l _e ^lo _d ^w _f ⁱ _o ⁿ _r ^g _th ^g _e ^{e -n1}

p^e6

r_e ^r5a- p^l _ar ^s _a ^c _t ^h _io ^e _n ^m _o ^e _{f e} ¹ _x ^, _a ^s _m ^ta _p ^r _l ^t _e ⁱⁿ _N ^g ₂ ^f ₃ ^ro _. ^{m example N35 and}

^{5 E Example N37}

P^x _re ^a _p ^m _a ^p _ra ^le _tio ^N _n ³⁷ _of ^m _in ^a _te ^y _r ^b _m ^e _e ^p _d ^r _ia ^e _t ^p _e ^a ₆ ^re ₆ ^{d folloig g l h 2.}

^{3-Bromo-5-chloro-pyrazolo[1,5-a]pyri}

^{idi (40 g 17.21 mmol}

1^{0 tetrahydrofuran (51.63 ml), diisopropyl i (14.47 l, 103.26 ) was dissolved in m mimxtoulr)e a wnads c pouprgpeedr(I w)it iohd niditerog (3e2n. Bis(triphenylphosphine)palladium m(ImI)o dli)ch wloarside ad (1d.e2d07 a gn,d 1 t.7he2 folmlopweerdatu bry prop-2-yn-1-ol (1.2068 m ml,g, 202..6155 m mmmool)l). T wheere re aadcdtieodn m unixdteurre n witraosge sntirr aetdmo astp rhoeorme te}

1_{5 w} ^{e for 20 hours. The mixture was concentrated under reduced pressure. The solid} c _frha

o_rs

m_{om f}

0_ailt

%_teorge

t_rd

o_{ap 1h o}

0_yff

0 _{o %v aen}

o_rd

f _{s t}

e_itlhihce

y_{al a g fi}

c_elt

e_lr,a

t_{a ute}

t_{sei)n w}

a_ga

n _hs

d_{e tp a}

h_tead

n_nseorb

u_{s ae}

i_nnd

g_{d d e o}

i_tchn

h_yto

l_{lor a s}

o_ci

m_elitc

e_aa

t_{te g aesl e alunednts pu (grirfiaeddien bty elu fltaiosnh (gravdeient elution from 0.2 % to 10 % of methanol). Th hane and methanol as eluents sol Snt m weatsho redm 1o:v MeHd+ u =nd 2e5r3 r,e RdTuc =ed 0.4 pre e product fractions were collected and the LCM 4s msuinre.}

2_{0 2}

P_{reparation of intermediate 67}

^{Intermediate 66 (5.81 g, 23.05 mmol) was - s1u6s6p- methanol ended in a mixture of dichloromethane and purged wit (h1: n1i,tr 3o1g0en m.l). Diphenyl sulphide (39 mg, 0.23 mmol) was added and the mixture was 5 was stirred under hydr Wogeetn P adt/mCo (s2p0% in weight of intermediate 66) was added and the mixture i antm woespighhetre of for in 2te0rm hoeudrisa.te Th 6e6 c)at waah}

l^ysere

s^{t a wd a}

a^dt

s^{e rodom}

r^{em aon t}

v^{dem or 14 hours. More wet Pd/C (20% ed tphe}

b^era

y ^{mture f}

f^{iltirxatutioren o wvas stirred under hydrogen} w_{ith a mixture of dichloromethane and methanol (4:1). The solvent} ^e _o ^r _f ^C _th ^e _e ^lite _fi ^® _ltr ^{and was washed} u_{nder reduced pressure and the residue was purified by flash chromatographayte o wvears s rielimoved 10 using dichloromethane and methanol as elue ca gel, T Yhieeld p nts (gradient elution from 0 % to 5 % of methanol.}

:_{r 3o.d3u9c3t g fractions were collected and the solvent was removed under reduced pressure. LCMS method o 2f: in MteHr+m =ed 2i5a5te, R 6T7 ( =582%.08)2 min}

P_{reparation of intermediate 68}

^{15 A ml) so wlu}

d^{ii atsio andd oefd m dertohpywlsiuslefo tnoy al m setha}

^{lf t (3139 g 1802 mmol) in dichloromethane (12 misxotuprreop wyalesth sytilrarmedine at ( 05°.3C11 fo mti}

r ^{1lr,re 3d}

h^1o.u2r3l

. ^{T mti}

h^{meo rle)f}

a ^{i int}

c^{ti doinchdimt 67 (3.052 g, 12.01 mmol) and N,N-} ₂₀ ^mloirxotu _n ^{reeth waane (24 ml) at 0°C. The reaction} a _sonld

r_{vife t}

i_cnh

a_te

t_{io w or}

n_agsan

i_{n t ri}

h_ec

e_{m la}

n_oy

e_ve

x_{erd w uansde wras rehdeudce wdith p wreastseur.re T.h Teh oerg caomicp loauy} ^s

n_e ^d

d_r ^il _w ^u

w_a ^te

a_s ^d

s _d ^w

u_ri ⁱ

s_e ^th

e_d ^{dichloromethane} d_{, f wiltiethreodut an fudrth thee pu r LCMS method 2: MH+t s =te 3p3.3, RT = 2.806 min}

2_{5 Preparation of intermediate 69}

^{Intermediate 68 (12.01 mmol), (S)-(+)-2-pyr -r167- carbon olidinemethanol (1.823 g, 18.02 mmol), sodium in N,N-adtiem (e3t.h8y1l9for gm,a 3m6.i03 mmol) and potassium iodide (1.591 g, 15.61 mmol) were suspended 5 reaction mixture was cdoeole (3d6 a mndl). th Tehe so relvaection mixture was stirred at 60ºC overnight. The a ecxetrtaacteted w wasith a add medixtu arned o tfh deic ohrlgoaronmicet lahyaenre/ wn}

m^at

e^{s w}

t^{h wa}

a^nas

o^{slh re}

(^em

9^do

:^{1 wve}

)^.itd

T^{hhe w unad}

c^otee

m^{rr. r}

b ^Te

i^{nhduced pressure. Ethyl eed a oqrguaenoiucs la lyayer was} d_{ried, filtered and the solvent was removed un} ^{ers were} b_{y flas der reduced pressure. The residue was purified 10 (gradiehnt co elluumtionn ch fromatography over silica gel using dichloromethane and methanol as eluents s Yoielvlde:n 1t. w1a2s removreodm un 0d%er t roed 1u0c%ed m preetshsanol). The product fractions were collected and the t5ho gd o 2f: in ure.}

L_{CMS me MteHr+m =ed 3i3a8te, R 6T9 ( =281%.48)0 min}

P_{reparation of intermediate 70}

^{15 t (e1r.t1-2B5ut gy,l-c 3h.3lo4rodimethylsilane (755}

^{g 501 l) dded to a mixture of intermediate 69 reaction was s mtirmreodl) a atnd ro torimeth tyelammpier (1.161 l, 8.35 ol) in dichloromethane (10 ml).The 0 organic layer was washed with water. Tahtuere or ogvaenricni lgahyte.r D wicahloromethane was added and the 2 r} _o ^e _v ^m

e_etr ^ov

h_{a s} ^e

n_ili ^d

o_cla ^u

)_{. g} ⁿ

T_e ^d

h_l ^e

e _u ^r _s ^r

p_i ^e _n ^d

r_og ^u

d _d ^c

u_i ^e

c_c ^d

t_{h flo} ^p

r_ar ^r _o ^e

c_tm ^ss

i_oe ^u

n_t ^r

s_h ^e _a ^.

w_n ^T

e_e ^h

r_{e a} ^e _{n cd} ^re

o_{l m} ^sid

l_ee ^u

c_tth ^e _an ^w _o ^a _l ^s _as ^pu _e ^r _l ⁱ _u ^fi _e ^es

n^{d d}

t_s ^bryied

(_g ^f,

r^l _a ^a _d ^{s fi}

i^hlte

e_n ^cre

t^od

e^{lu and the solvent was} m _lu ^m _ti ⁿ _on ^ch _fr ^r _o ^o _m ^ma ₀ ^t _% ^og _t ^r _o ^ap ₅ ^h _% ^y p_{ressure. ed and the solvent was removed under reduced 25 Y LCieMldS: 7 m75et mhogd o 2f: in MteHr+m =ed 4i5a2te, R 7T0 ( =512%.81)9 min}

P_{reparation of intermediate 71} -168-

A ^{the mix mtuixretu oref.1, I4n-tdeiroxane and water (}

^{3110 l) dg d by bubbling nitrogen gas through dioxaborolan-2-yl)pmheendoialte (49700 (775 g, 1.72 l), 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2- 5 mg, riphenylphosphine)palladium(0) (35 mmol 0).0 a3nd m pmotoals)s,iu 2m-di pchyoclsophheaxty m}

e^lpg

t^rh,

i^{boas 2p.06 mmol), tetrakis(t}

s^{ihcin (o3-2’,4’,6’-triisopropylbiphenyl (Xphos) (33 mg, 0.07 nitrogen gas at 85°C for 16 hours. The reac etiqo.n) w meixretu aredd wed and the mixture was stirred under} a_{nd the organic layer was washed with water. The organ} ^a _ic ^{s c} _la ^o _y ^o _e ^le _r ^d _w ^. _a ^E _s ^th _d ^y _r ^l _ie ^{acetate was add} _th ^e _e ^d _{10 c solvent was removed under reduced pressure. The residue was purifiedd, by filte flaresdh a cnodlumn eh}

e_lur

m_toioom

v_na

e _ft

d_{roography over silica gel using dichloromethane and methanol as eluents (gradient r umnd 0er % re todu 5ce %d o pfr methanol). The product fractions were collected and the solvent was LCMS method 2: MH+ = 48e3s,s RuTre =.1.836 min}

1_{5 Preparation of intermediate 72}

I ^{pnutergrmeded wiaitthe n 7i1tro (8g5e1n. m Wg,et 1. P7d6/C mm (1}

^{0l)%, 85 gp, 1.d76d) i thddoeld (5 a.2n8d m tl) and the mixture was 0 under hydrogen atmosphere at room temperature for 15 hours. The cahtaely mstix wtuarse re wmaso stirred 2 f} _T ^il _h ^{tration over Celite® and was washed with a mixture of dichloromethane and methanovle (d4:1 b)y.} f_{laseh s cohlvreonmta of the filtrate was removed under reduced pressure and the residue was purified by eelumtioovne fdro umnd 0to}

e_{r %gra}

r_{e toph}

d_{u 8y}

c_{e % over silica gel, using dichloromethane and methanol as eluents (gradient r d o pfre msesuthraen.ol). The product fractions were collected and the solvent was} ^{Yield: 402et mhogd o 2f: in Mt -169- LCMS m eHr+m =ed 4i8a5te, R 7T2 ( =472%.81)1 min}

P_{reparation of intermediate 73}

5 ^{T soelturatibounty olafmmonium fluoride (1M}

^{lti i tt hyd f , 1.0 ml, 1.0 mmol) was added to a mixture was in stteirrrmeded aita rtoeom 72 te (m402 g, 0.83 l) i tt hydrofuran (2.49 ml). The reaction and washed with water and ap searatuturarete fdor 16 hours. The mixture was diluted with ethyl acetate} _{10 l e} ^e

a_{adydeerd w,a thse d srioeldid, w filatesre fidlte arnedd t ahned s dorliveedn utn wda} ^a

e_s ^q

r _r ^u

r_em ^o

d_uo ^{us sodium bicarbonate solution. The organic} c_{veedd under reduced pressure. Acetonitrile was YieMldS: 2 m32et mhogd o pressure.}

L_{C 2f: in MteHr+m =ed 3i7a1te, R 7T3 ( =851%.81)4 min}

1_{5 Preparation of example N37}

A

d^{e sgolution of intermediate 73 (182 g, 0.49 l) i 2 thyltetrahydrofuran (20 ml/mmol) was 20 azodaiscsaerdbox byylate bu (b2b9ling nitrogen gas through the mixture. A solution of diisopropyl n ait proegrieond g oafs 3 t hhorouursgh1}

a^{t th 9e m m}

0^{° mg,}

C^{ix 1}

t^{tou.4r ae7. d Beom}

g^{tol) in toluene (20 ml/mmol) was degassed by bubbling ahss seodlut sioonls were added simultaneously and dropwise over} i_{n tsol cuoeonleed (7 a5nd m tl/hmem soollv).e Tnhte wa msix rteumreov weads u sntidrer} ^u _e ^t

r_d ^ion

r_{e adt} ^o

u ₉ ^f

c₀ ^{triphenylphosphine (386 mg, 1.47 mmol)} w_{a e°dC p froerss 3u0re minutes. The reaction mixture flash column chromatography over silica gel using heptane an.d Th eeth ryelsid auceet was purified by 25 ( agsra edluieenntts el (ugtriaodnie frnotm elu 0ti %on to fro 5m0 % 0 % of to et 1h0yl % ac oefta mtee)th foalnloowl).ed Th bey p driocdhulocrto fmraectthioa e ts nnseat}

w _ae

e_{nrd as e m coeltlu lhe ean ctneodl} ^{a pnhdas tehe co sluomlvenn cth wroamsa rtemoved under reduced -1 p7r0e-ssure. The residue was purified by reversed solvent was remo ography (HPLC method A). The product fractions were collected and the Y ved under reduced pressure.}

5 _LC ^ie _M ^ld _S ^{: 3} _m ²⁸ _et ^m _ho ^g _d ^o ₂ ^f _: ^e _M ^xa _H ^m+p ₌ ^le ₃₅ ^N ₃ ³ _, ⁷ _R ⁽ _T ¹⁹ ₌ ^% ₂ ⁾ _{.061 min}

E _{Exa ple}

i_llxuam

s_{mtraptlee N}

d _N3

f_o38

r_{8 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N3 g0e.n Tehrael p srcohdeumcte w 1as an odbta aicnceodrd ainsg th teo H thCel s parlot.cedures}

^{10 E}

E^xampl

i_ll ^x _u ^a _s ^m _tra ^p _t ^le

e^{e N}

d ^N3

f_o ³⁹

r⁹ _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^fo _a ^l _m ^low _pl ⁱ _e ⁿ _s ^g _N ^g ₂ ^e ₇ ^ne _a ^r _n ^a _d ^l _N ^sc ₈ ^h _. ^{eme 1 and according to the procedures}

^{15 E Ex p}

i_ll ^xa

u^amm

s_tra ^ple

t^l _e ^{e N}

d ^N4

f⁴⁰

o⁰ _{r t} ^m _he ^ay _pr ^b _e ^e

t_{ead of a tert-butyl dpia} ^p

m_r ^r _a ^e

e_t ^p

t_iho ^a

y_n ^re

l_{s o} ^d

i_lf ^fo

y_{l e} ^l

p_x ^l

r_aom ⁱ

t_epcl ^g

t_e ^g

i_{ng N g8ro uuspi} ^l _n.g ^h

T_{h ae t perrot-db} ¹

u_u ^a

c_ty ⁿ

t_l ^d

w _d ^a

a_isp ^c _h ^c

o_e ^o

b_n ^rd

t_ay ⁱ

i_l ⁿ

n_si ^g

e_lydl ^to

a _p ^{the procedures} i_{ns sro thteect HinCgl s garoltu.p}

20

^{Exampl -171- E ilxamplee N N4411 may be prepared following general scheme 1 and according to the procedures} i_n ^lu _s ^s _te ^tr _a ^a _d ^te _o ^d _{f a} ^{for the preparation of example N8 using a tert-butyl diphenylsilyl protecting group} 5 _{tert-butyl dimethylsilyl protecting group.}

P_{reparation of intermediate 74}

A ^{25. s5o2lut mionmo olf) 1 wNas hex aadmdeedthy dldroispilwaizsaene}

^{di p litd i fnh 1y5dro muisnu tetetrsah tyodro afu srauns (25.52 ml, 10 methyltriphenylphosphonium iodide (10.316 g, 15.52 mmol) in anhydrous tetrahydproefnusraionn (7 o5f m(+l))-3 a-tb -o2c0-2 to,2 -25°C and the mixture was stirred at 20 to -25°C for 15 minutes. A solution of (R)- tetrahydrofura-dnim (7e5th myllo)x waazosli addine-4-carboxaldehyde (4.50 g, 19.63 mmol) in anhydrous} 5 ^{stirred at 0°C for 5 hours andd aetd r doroompw tiesmep oevreartu are pe friod of 15 minutes and the mixture was} _{1 c moixotleudre t woa 5s°C stir arendd f aonr 1 a0qu meionuustes s.at Tuhrated ammonium} ^or _ch ¹ _l ⁶ _ori ^h _d ^o _e ^ur _s ^s _o ^. _lu ^T _t ^h _io ^e _n ^re _w ^a _a ^c _s ^tio _a ⁿ _dd ^m _e ⁱ _d ^xtu _a ^r _n ^e _d ^w _th ^a _e ^s e_{t e product was extracted with a mixture of heptane and sohlvyeln atce wtaatse ( r1:1). The combined organic layers were washed with brine, dried, filtered and the chromatographeym oovveerd s uilincdaer ge rled uusiced pressure. The residue was purified by flash column 20 f rreommov 0e %d u tnod 15 % of ethyl acetate)n.g Th heep ptraondeuc atn fdrac ettihoynls a wceertaete co allsec eteluden atnsd ( tghread sioelnvten etlu wtioans Yield: 3.80 ge orf i rnetdeurmceeddi partees 7s4ur (e8.5%)}

P_{reparation of intermediate 75}

^{25 p} _in-_t ^T _e ^o _rm ^lu _e ^e _d ⁿ _i ^e _at ^s _e ^u ₇ ^lf ₄ ^on ₍ ⁱ ₃ ^c _.6 ^a ₀ ^ci _g ^d _, ^m ₁₅ ^o _. ⁿ ₈ ^o ₄ ^h _m ^yd _m ^ra _o ^t _l ^e _{) i} ⁽ _n ^1.0

⁸⁴ _th ^{g, 5} _l ^.7 ₍₁ ⁰ _{58 m} ^o _l) ^l _. ⁾ _T ^w _h ^a _e ^s _r ^a _ea ^d _c ^d _t ^e _io ^d _n ^to _mi ^a _xt ^s _u ^t _r ⁱ _e ^rre _w ^d _as ^so _s ^l _t ^u _ir ^t _r ^io _e ⁿ _d ^o _a ^f _t ^{room temperature for 16 hours. To the reacti -o1n72 m- The volum ixture was added sodium bicarbonate (1 ml). acetate aned w waaste rre.d Tuhcee adq tuoe 10 ml under reduced pressure. The residue was dissolved in ethyl} 5 _{layers were washed with bri} ^o _n ^u _e ^s _, ^l _d ^a _r ^y _ie ^e _d ^r _, ^w _f ^a _il ^{s extracted with ethyl acetate. The combined organic} p_{ressure. The product was used without futrethreedr p aunrdific tahteion so inlve thnet n weaxst s rteemp.oved under reduced Preparation of intermediate 76}

^{10 Ibm l}

7^ui

5^tdya

(^l1(zco

5^{h.8leo4ro (1) md.4imp0h2}

o^{el)n gy,}

i^{nls 2il0}

d^a.

iⁿ⁵

c^e9

h^{lo (4 m}

r^o.5m

m^6o

e ^gl)

t^h,,

a ¹⁴

n^{7e.(4d2i thyl}

(^{31 mll) i )py}

) ^{ddidid to ( a38 s7tirr medg, so 3l.u1t7ion m omfo inl)te armnded tieartte- temperatur . The reaction mixture was stirred at room} f_{iltrate was} ^e _w ^fo _a ^r _sh ⁷ _e ² _d ^h _w ^ou _ith ^rs. _w ^T _a ^{he solids were filtered off and washed with dichloromethane. The} _{15 reduced pressure. The residteuer a wnads b priunreif,ie dried, filtered and the solvent was removed under u Tshieng pr hoedputcatn fera acntidon esth wyelr aece ctoallteec atesd e alunedn tthse (dg sr b}

o_ay

l_{dveie fl}

n_na

t_tsh

w _{ealu c}

s_{toilumn chromatography over silica gel roenm forovmed 0 u %nd to 10 % of ethyl acetate). Yield: 6.20 g of intermediate 76 (92%) er reduced pressure. Preparation of intermediate 77}

^{20 A stir sroelduti}

m^{onixt oufre int oefrm trieflduioartoea 7c6et (ic6.2 a0ci g, 14.57 l) i dihl methane (10 ml) was added to a} w_{as stirred at room temperature for} ^d _{2 ho} ^d _ur ^d _s. ⁱ _T ^h _h ^l _{e solv} ^t _e ^h _{nt wa} ⁽ _s ¹ _r ^:1 _e ^{, 130 ml). The reaction mixture} T _{sohleuti roensi wduaes a wdadsed di pssoortlivoendwi isne. d Tichhelo mroimxteutrhea wnea.s A sntirr aeqdu aetou rosm}

o_{m soavt tue}

e_rd

m_{at u}

p_en

e_dde

r_{a sr}

t_{uo r}

r_de

e_iduu

f_{mced pressure. 25 or 3 b0ica mrbinountaetse.} ^{The two layers were separated and the orga -n1i73- sodiu c layer was washed with an aqueous saturated underm re bdicarbonate solution. The organic layer was dried, filtered and the solvent was removed} Y_{ield: 4.32} ^uc _g ^e _o ^d _f ^p _i ^{ressure. The product was used without further purification in the next step.} 5 _{LCMS method 2n:t MerHm+e =di 3a2te6, 7 R7T (9 =1% 2.7)85 min}

P_{reparation of intermediate 78}

^{10 m A mixtur}

b^{umteonl)e i (ne}

1^{. a o}

1^cf

6^{e4t ion}

m^nteiltr

,^{rmi 1leed}

2^{.5 (i3a}

9^7te

m^.7m777

o ^{m (4.10 g, 12.59 l) d pt ium carbonate (1.74 g, 12.59 l)l) was adtdiedd andt the rea tctiopn mti e for 30 minutes.4-Bromo-1- hours. The mixture was cooled to room temperature. The solidxstu wreer wea fsi stirred at 90°C for 16} with ethyl acetate. The solvent of the filtrate was removed under reduced^l p^tere^res^ds ^{off and washed} _{15 was dissolved in ethyl acetate and was washed with an aqueous saturated sod}u_iure_m. T _bh_ice_a residue s_{olution and brine. The organic layer was dried, filtered and the solvent was removedrb uonndaete r r LeCdMucSed m pertheossdu 2re:. M THh+e = p 3ro8d0u,c RtT wa =s 3 u.0s7e2d m wiinthout further purification in the next step. Preparation of intermediate 79}

^{20 A ad sdoelduti dornop owfi tseert- tbou ato sxtyircraerdbo snoylult}

^{i hydf iidt (27d5i gt 17285 (912.59 ml)m ino tetrahydrofuran (7 ml) was} m_{l, 18.88 mmol) in tetrahydrofuran (30 ml). The solution was stirred a} ^l) _t ^{and triethylamine (2.624} h _{hoeuprtas.ne Th (e8:2 s)ol wveanst a wdadsed re.m Tohvee odrg uanndiecr la reydeurc weads p wreassshuered a wnitdh a an m aixo}

q_{tu r}

u_reeom

o_{u osf te em}

s_tahp

t_{ye ulrature for 16 25 ra atceedta stoed aiunmd} ^{b reicmaorbvoenda utend seorlu rteiodnuc aendd pr bersinseu.re T.h Tehe or rgeasnidi -c17}

u^{e la4}

w^{y-ears w puarsifie ddrie bdy, f flialtsehre cdol aunmd the solvent was over silica gel using heptane and ethyl acetate as eluents (gradie n chromatography} e_{thyl acetate). The product fractions were collected and th} ^{nt elution from 0 % to 7 % of} 5 _{r Yedu u e solvent was removed under LCieMldc}

S_{:e 3d}

m_{.7 p}

e_5re

t_{h gs os}

o_dfr

2 _ine

:_t.

M_{erHm+e =di 3a8te07 (M9H (6+2 -% B)oc), RT = 4.238 min}

P_{reparation of intermediate 80}

^{10 D caictahllyosrotm (seetchane was refluxed und}

^{it g t ph f 2 hours. A solution of Grubb’s solution of inotnedrm geedniaeration, 310 g, 0.37 l) i dihl thane (10 ml) was added to a 15 atmosphere. The te 79 (3.52 g, 7.34 mmol) in dichloromethane (279 ml) under nitrogen M} _un ^o

e_d ^r

s_e ^e

s_r ^G

u_{r n} ^{r reaction mixture was stirred under nitrogen atmosphere at 30°C for 16 hours.} e_it ^u

._r ^b _o ^b

T_g ^’

h_e ^s

e_n ^c

r _a ^a

e_t ^t

s_m ^aly

i_do ^s

u_s ^t

e_ph ^(s

w_e ^e _r ^c

a_e ^o

s _a ⁿ

p_t ^d

u ₃ ^g

r_i0 ^e

f_i° ⁿ

e_C ^er

d _f ^a

b_o ^t

y_r ^io ₁ ⁿ

f_l6 ^{, 0}

a_{s h} ^.

h_o ⁰ _u ³ _. ^q

c_ros ^e

l_{um T} ^.) _h ^w

n_e ^{a a}

c _s ^s

h_orolv ^d

m_e ^d _n ^e

a_t ^d h_{e to w} ^a

g_ra ⁿ

a_s ^d

p_{h re} ^th

y_m ^e

o_ovv ^m

e_e ⁱ

r_d ^xtu

s _u ^r

i_lin ^e c_d ^w a_er ^as g_{e re} ^s l_d ^t _u ^ir _c ^re _e ^d p_{r d prptane and ethyl acetate as eluents (gradient elution from 0 % to 5 % of ethyl ace using Yioedldu:c 1t. f9r0ac gtio onfs in wteermree cdoiallteect 8e0d ( a5n7d% t)he solvent was removed under reduced pressuret.ate). The 20}

P_{reparation of intermediate 81}

^{A stir sroeldut mioinxt oufre in otefr trmifleudoiraoteac 8e0tic (1 a.c9i0d a gn,d 4. d2i1ch m -1}

l^om7

r^oo5

m^{l-)e itnha dniceh (l1o:r3o,m 4e7th maln).e T (h1e0 r meal) was added to a stirred at room temperature for 2 hours. The mixture was diluted with di ction mixture was} w_{ashed with water, an aqueous 1N sodium hydroxide solution and brine. T} ^{chloromethane and} 5 _{d wriitehdo,ut fil ftuerrtehder a pnudrif the solvent wasxt removed under reduced pressure. Thhee p orrogdauncitc w laayser u wseads LCMS method 2: MiHca+t =io 3n5 in2, th ReT n =e 2.9 s1te7p m.in}

P_{reparation of intermediate 82}

^{10 A inte mrmixetduriaete o 8f12 (1-(.t5e0rt- gb,u 4to.2x6yc marmbool}

^l

i^{odide (1.081 g, 6.51 mmol) in N,N)y}

-^,l

d^imedi

t^{i )thy}

h^{ylformbamidtth}

e ^{( (215.5 m93lfo}

l^{) gn}

w^,a

a ^1t

s^{5e.03 (1. m2m0ol g), an 5d.0 p1ota msmsiuoml), The reaction mixture was poured into water and extracted weith y sltirred at 60ºC overnight. 15 o} _s ^{g w}

c_o ^r

h_lrv ^a

o_e ⁿ

m_n ^ica

a_{tt w} ^l

o_ga ^y

r_s ^ers

a_{p rehm} ^e

y_o ^r

o_v ^e

v_eed ^dri

r _{s u} ^e

i_n ^d

l_icd ^,

a_e ^fi _r ^lte

g _ree ^re

l_d ^d

u_usc ^a

i_e ⁿ

n_d ^d

g _p ^t

h_r ^h

e_e ^e

p_sts ^s

a_u ^o

n_r ^l

e_e ^ve

a _a ⁿ

n_n ^t

d_d ^wa

e _th ^s

t_he ^re

y_{l re} ^m

a_s ^{o eth}

p^{r acetate. The combineed} i_d ^v _ue ^d _w ^un _a ^d _s ^e _u ^re _ri ^d _fie ^u _d ^ce _b ^d _y ^p _f ^r _l ^e _a ^s _s ^s _h ^ur _c ^e _o ^. _lu ^T _m ^h _{n from 0 % to 40 % of ethyl acetate). The product fractio cetate as eluents (gradient elution 20 remove ns were collected and the solvent was Y LCieMld 1d}

S_{: m.1 u}

e_6n

t_{h gde}

o_{d orf r}

2 _ie

:_nd

M_{teuced pressure.}

H_{rm+e =d 4ia9t5e, 8 R2T ( =473%.3)74 min}

P_{reparation of intermediate 83} -176-

I ^{dnictehrlmoreodmiaetteha 8n2e (1 (1:3.1,610 g m,l) 2.34}

^{l) ti d i iture of trifluoroacetic acid and An aqueous 1N sodium hydr.o Txhidee r soluttiion wiast added toti thed re aatc room temperature for 2 hours.} 5 _{p arnou}

u_dd

r_{ifi tchc}

a_{et w}

t_{io snoalsvnx}

i_{ne e}

t_httr

e _wac

n_at

e_sed

x_{t re wmitohve ddich ulnodroemre rethdauncee.d T phrees csoumreb.in Tehde o prrgoadn} ^ti

u_i ^o

c_c ⁿ

t _la ^m

w_yae ^ix

s_r ^t _s ^ur

u_{s w} ^e

e_e ^u

d_re ^{ntil pH 11. The} w _{ditrhieodu,t f fiultretrheed p r LCMS method 2: MH+ s =te 3p9.5}

1_{0 Preparation of example N41}

T

p^{rheepa sruabtisoenq oufe Nnt8 s atnedps us tiong o ibnttearinmediatep 8l3. N T4h1e produ bct wdas o onbta thineed pr aosce thdeur HeCsl u ssaeltd. for the} _{15 E Exm}

a_cxa

c_aomp

r_dpl

i_le

n_{e N}

g _N4

t_{o422 the m paryoc beed purreepsa ilrluedstr faotlelodw fionrg th geen pereraplar sacthioenm oef e 1x,a smtaprltein Ng1 f1ro.m example N38 and}

_{Example N43}

^E _x ^x _a ^a _m ^m _p ^p _l ^l _e ^e _N ^N ₃ ⁴ ₈ ³ _. ^{is obtained as a side-product d -u177-} e ^{ring the Mitsunobu reaction in the preparation of}

^{5 E Exm}

a_c ^xa

c^a _o ^mple

r_d ^p _i ^l _n ^{e N}

g ^N4

t_o ⁴⁴⁴ _the ^m _p ^a _r ^y _oc ^b _e ^e _d ^p _u ^r _r ^e _e ^p _s ^a _il ^r _lu ^ed _str ^f _a ^o _t ^l _e ^l _{d f} ⁱ _or ^g _th ^g _{e prep} ^l _arat ^h _{ion of e} ¹ _x ^, _a ^s _m ^ta _p ^r _l ^t _e ⁱⁿ _N ^g ₁ ^f ₁ ^ro _. ^{m example N43 and}

1^{0 E Exm e N}

i^l _n ^lxa

u^a

s^smpl t_e ^tr _a ^ap

d^tlee

o^{d N4} f _a ^fo45 t^r5

e ^t _r ^{h m}

t-^eay

b_u ^p _t ^{r b}

y^ee

l^p _d ^{a p}

i_m ^rrae

e^{tpioared following general scheme 1 and according to the procedures} i _th ⁿ _yls ^o _il ^f _y ^e _{l p} ^xa _ro ^m _te ^p _c ^le _tin ^N _g ² _g ⁰ _ro ^u _u ^s _p ⁱⁿ _. ^{g a tert-butyl diphenylsilyl protecting group} P_{reparation of intermediate 84}

^{15 A} _mm ^m _o ⁱ _l ^x _), ^tu ₄ ^re _-(d ^o _im ^f _e ^m _th ^e _y ^th _la ^y _m ^l _i ⁽ _n ² _o ^R _)p ^)- _y ² _r-_id ^(t _i ^e _n ^rt

^b

c_{hloromethane (135.48 ml) w (5a5} ^{t y}

s _{cgo,o 4} ^b

l_e.5d2 ^{yl i}

t_{o 0l)} ⁾³

°_Cd ^h

u _i ^yd

n_diedra ^x _z ^y _o ^-p

n_lie ^ro

t_{ro (} ^p

g₄ ^a

e_.6 ^{noate (9.90 g, 45.16} d_{i n12 a gt,m 6o7s.p7h4e mrem.o tle)r itn-} ^{Butyl(chloro)diphenylsilane (12.919 ml, 4 -178- min 9.68 mmol) was added dropwise over a period of 15 withu dteicsh.l The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was diluted} 5 ^{aqueous soarotumraettehdan seod aind was washed with an aqueous 1N hydrochloric acid solution and an} u _{gnedle ursi rnegdu hceepdta pnrees asnudre} ^u _. ^m

e_{t Thh} ^b

y_e ^ic

l _{a r} ^a _e ^r

c_s ^b

e_i ^{onate solution. The solvent of the organic layer was removed} t_{dautee w asas el purified by flash column chromatography over silica acetate). The product fractions were collecuteendts an (gdra thdeien st elution from 0 % to 15 % of ethyl pressure. Toluen olvent was removed under reduced LCM e was added and removed under reduced pressure.}

1_{0 S method 2: MH+ = 358 (MH+ - Boc), RT = 2.269 min}

P_{reparation of intermediate 85}

A ^{stirred solution of int}

1^{5 was cooled to -78°C uenrdmeerd niaitrtg 84 (2t1.0 gp,h 45.8.9 Di l) i hydrous diethylether (137.67 ml) ( m1}

m^iM

e^{xtthu in}

a^{re te}

n^{o wtr}

l^aa

(^5shy

.^{5 sdt mirrorfu}

l^e).dra

T ^an

h^t,

e ^{- 5}

m^758.0

i^{x°tC7 m}

u^{re fomro}

w^{a 1l) dd}

s ^{h so w}

t^iua

r^rrs

e^{.d T ah aee}

t ^{rdea oi}

c^vteiorb

n ^aty

w ^pl

a^el

s^{rio qdin}

u^{e ou}

n^fm

c ^{3 h}

h^0y

e^{d mdriide solution (DIBAL) bnyute sslo.w Th aedd reitiaocntio onf} p _{roooumred tem in} ^{-78°C for 15 minutes. The cold solution was} _{20 ptoer aantur aequ foerous saturated Rochelle salt solution (2 mdl:1 the m pmroodlu DcItB wAaLs) e axntdra scttierrded wi atht e sothl tvy}

h_el

e_{n atc we}

x_ataste

t _{re.m Tohveed co 3}

u_m.5

n_{b The layers were separated}

d_{i h}

e_no

r_eu

r_drs

e_{d o.}

u_{rcg an}

e_{adni pcre lasyseurrse. w Tehree p wroadsuhcetd w wasith us berdin we,ith doriuetd f,ur ftihlteerre pdur aifnicdat tihoe i n Pnrepar naetiotn s oefp i.ntermediate 86}

^{Methyl (2R)-2-aminopropanoate hydrochlorid -e17 (9- mixture of inte 4.80 g, 34.42 mmol) was added to a stirred mmol) in dichlorrmoemdeiathtean 8e5 (1 (3475..6879 m mlmol) and N,N-diisopropylethylamine (12.024 ml, 68.84 5 hours. Sodium triacetoxyborohydride) (.14 T.h5e91 m gix,tu 6re8.8 w4as m smtiorred at room temperature for 16 r weiathct dioicnh mlorixotmureeth waanse s atnirdre adn a atq rouoemou tsem 1Npe hryadture for 5 hours. Tl)he wa resac atdiodned mi pxtourrteion wwaisse d.ilu Tthede The mi rochloric acid solution (75 ml) was added slowly.} a_{nd the} ^x _o ^tu _r ^r _g ^e _an ^w _ic ^as _la ^s _y ^t _e ^ir _r ^re _w ^d _as ^at _w ^r _a ^o _s ^o _h ^{m temperature for 10 minutes. The two layers were separated} _{10 organic layer was dried, filtereded an wdith th aen s aoqluveenotus saturated sodium bicarbonate solution. The r aecseidtautee a wsas elu peunritfsied (gr baydi felansth el cuotilounm fnro cmhr 5o%ma ttoog 5r0a w}

%_pahs

e_{y r}

t_{h oe}

y_vm

l_{e arov}

c _se

e_iltid

a_{cta un}

e_{) gd}

._ee

T_lr

h _{ues re}

p_{induced pressure. The rgod huecptt farnaecti aonnd ethyl collected and the solvent was removed under reduc s were Yield: 16.30 g o ed pressure.}

L_{CMS f intermediate 86 (69%)}

1_{5 method 2: MH+ = 515}

P_{reparation of intermediate 87}

Iⁿ

2^{0 0°tCer umneddeiart neitr 8o6ge (2n.6 a0tm go,s 5p.h0e5re.l T)ifl di tli di id ( dihl thane (15.1o5nw mils)e a.n Tdhe co reoalecdtio to m n aqixuteuoreus w saastu srtairtreedd s a 4 l) dded porti}

o^{tdi ruomom bic teamrbpoenraatteur se for 3 hours. The reaction was slowly poured into an} T_{rhieed a,q fiulteeoreuds a lanyder th wea ssol evxetnratc wteads w reitmh} ^o

o _d ^l

v_i ^u

e_c ^t

d_h ^io _lo ⁿ

u_rno ^a

d_m ^nd

e_ert ^s _h ^t

r_ea ^ir

d_n ^re

u_e ^d

c_{.e T} ^{at room temperature for 30 minutes.} d _{dh pere csosmubrein.e Tdhe org parondicuc latyers were 5 w LCithMoSut m fuertthhoedr p 2u:r MifiHca+t =io 4n1 in5 the next step. was used 2}

P_{reparation of intermediate 88} -180-

T^r

m^{mieothl)yl ianm dinicehl (o2r.o1m0e mthla,n 1e5. (1155.15 ml)l). The rdedacdtio tn mixttiurd ltion of intermediate 87 (5.05} T_{he reaction mixture was used dire} ^{e was stirred at 40°C for 16 hours.} 5 _{ctly in the next step.}

P_{reparation of intermediate 89}

A ^{ad sdoelduti}

^{as 10 se poonti oofn te wrti-sbeut tooxy aca srtbir dyl lhytididf (1 it32 gd 6i0t688 (l5). i05 dihmloorlo,m creutdhean fero (m15 p mrel)vi wous dtinlup}

d^te).

a^{d T}

n ^wh

a^qite

u^{h r}

e ^de

o^iuca

s^hclt

s^oio

a^{rnotum m}

r^aei

t^tx

e^ht

d^aunre

s^{e w}

o^{d aa}

i^uns

m^{d s wtir}

b^iar

c^sed

a^{r wboa a}

n^st

a^{h r}

t^eo

e^{dom temperature for 16 hours. The reaction was a s woliuthtio ann. T ahqeue oorugsan 1icN la hyyedrro dcriheldo,ri fcilt aecreidd solution} s_{olvent was removed under reduced pressure. The residue was} ^{and the} c_{hromatography over silica gel using hepta purified bgy flash column 15 f rreommov 0e %d u tnod 5e0r r %edu ocfe edth pyrle ascseutate). The prondeuc atn fdrac ettihoynls a wceertaete co allsec eteluden atnsd ( thread sioelnvten etlu wtioans YieMldS: 1 m.9e5th go odf 2 in:t ReTrm =e 4d.ia9t2e38re.}

L_{C m9in (80%) 20 Preparation of intermediate 90} -181-

I ^{anntedrm ceodoilaetde 8 to9 ( 05°.C35 u gn,d 11.0}

^{8 l) di l d i hyd tetrahydrofuran (33.24 ml) tetrahydrofuran, 5.89 ml, 7e7r.56i mtmgol) wats addpehd po.rt Bio di thysulfide (2N solution in 5 u} _re ⁿ _a ^d _c ^e _t ^r _io ⁿ _n ^it _m ^ro _i ^g _xt ^e _u ⁿ _re ^a _w ^tm _a ^o _s ^s _c ^p _o ^h _o ^e _le ^re _d ^a _to ^t ₀ ⁰ _° ^° _C ^C _a ^fo _n ^r _d ³ _m ⁰ _e ^m _th ⁱ _a ⁿ _n ^u _o ^te _l ^s ₍₄ ^a ₀ ⁿ _m ^d _l) ^antw

w ^ris

a^oe

s^{o. The reaction mixture was stirred} a^m _dd ^te _e ^m _d ^p _d ^e _r ^{rature for 16 hours. The} s_{tirred at room temperature for 1 hour. The solvent was removed undeorpw reidseu. The mixture was the residue was co-evaporated twice with methanol. The product was usecded w pitrheosustur fe and 10 purification in urther LCMS method th 2e: M neHx+t s =te 4p6.9}

P_{reparation of intermediate 91}

^{15 Ay}

^{-dioxoisoindolin-2- alt)mac m}

o^ei

s^tx

p^atu

h^ldr

e^ee

r^{ehy of}

a^{dte ro (4 in}

o^.t

m^9e6rm

t^{e gediate 90 (6150 g 1312 l) and 2-(1,3}

m^{, 2p6e.r2a4ture folr) 1 i6 d hihl th (39.36 ml) was stirred under nitrogen mmol) was added portionwise. The reactionou mrs. Sodium triacetoxyborohydride (4.171 g, 19.68 The reaction mixture was quenched by thixetur aed wdiatis stirred at room temperature for 1 hour.} b_{icarbonate solution. The water layer was extracted} ^on _wit ^o _h ^f _d ^a _ic ⁿ _hlo ^{aqueous saturated sodium} _{20 o rergdan}

i_{uceicd la pyreesrssu wree.re Th wea rsehseiddue wit wha bsri pnuer,ifi derdied b,y f fillatesrhed co alunmdn th cehr sooro}

m_lvm

a_etne

o_tth

g_{r wane. The combined aapshy re omveoved under useng pr hoedputcatn fera acntidon esth wyelr aece ctoallteec atesd e alunedn tthse (g sroaldveienntt w ealusti roenm forovmed 0 u %nde tor 4 re0d %uce odf e ptrheyr}

s_{l s s ai uclica gel Th reet.ate).} ^{Yield: 6.80 g of intermedia -182- LCMS method 2: MH+ = 64te2, 9 R1T (8 =1% 3.3)77 min}

P_{reparation of intermediate 92}

5 ^{A 0.5 m0ix mtul,re 15 o.f66 int mermmoeld)i iante et 9h2an (}

^{6l.7 (053 g, 1l)0.44 ti l)d td 70 hyCd f i 4 h (o5u0r/s6.0 T%he aq reuaecotuiosn s moluixttiuorne, w}

0 ^{etahsyl c aocoeletadte a.n Tdhe th seo slvuesnpte onfsi tohne w filatrsate filt weraesd to remove the solid. The solid was washed with 1 was re-dissolved in ethyl acetate. The orga renmico lvaeyder un wdaesrh reeddu wceithd p arnes asquureeo aunsd 1 thMe r seosdidiuume} h _{reyddurocxeidde pr seoslsuutiroen.. T Thhee pr oordguacntic wa lasy uesre wda ws dried, filtered and the solvent was removed under LCMS method 2: MH+ = 512 ithout further purification in the next step. 15 P}

p _Trhre

e_epa

p_{a frora}

a_llt

t_oio

i_own

n_{in o}

o_{gf e}

f _{N sx}

2_taem

0_{p asple}

n_{d to N4}

u_{s o5}

i_{nbgta iinnte ermxaemdipaltee 9 N24.5 are based on the procedures used for the}

2^{0 E Exam}

a_c ^x _c ^a _o ^mpl

r_d ^p _i ^le

n^{e N}

g ^N4

t_o ⁴⁶⁶ _the ^m _p ^a _r ^y _oc ^b _e ^e _d ^p _u ^r _r ^e _e ^p _s ^a _il ^r _lu ^ed _str ^f _a ^o _t ^l _e ^lo _d ^w _f ⁱ _o ⁿ _r ^g _th ^g _e ^en _p ^e _re ^ra _p ^l _ar ^s _a ^c _t ^h _io ^e _n ^m _o ^e _{f e} ¹ _x ^, _a ^s _m ^ta _p ^r _l ^t _e ⁱⁿ _N ^g ₂ ^f ₃ ^ro _. ^{m example N45 and} -183-

E ^{Ex 7}

P^xa

r_e ^am

p^{mple N4}

a^p _ra ^le _tio ^N _n ⁴⁷ _of ^m _e ^a _xa ^y _m ^be _ple ^pr _N ^ep ₄ ^a ₇ ^{red foll ig g l h 1, tarting from example N45.}

^{5 E dixsasmolpveled N in451,2 (1-d2i0ch mlogro,e 0th.3a1ne m (2}

^{l)l). Cdppyl(IpI)pylbtt (1i13 ac midg, (500.6 m2g m,m 0o.6l)2, mmol) were (97 mg, 0.62 mmol) and sodium carbonate (2.0 eq., 131 mg) were added. 2,2’-bipyridyl 10 stirred at the open air at 70°C for 16 hours. The reaction mixture wa The reaction was o 3f0 a mnin auqtueeso.u Tshe sa mtuixrtautreed w aamsm doiluntiuemd w cihthlo driidcehlo solution and was stirresd q auten rocohmed te bmyp theera atudrdeiti foonr threine o.rg Tahneic o largyaenric wa lasye wras whaesd d wriiethd, an aqueoruosm seathtuarnaete.d Th aem tmwoon liauymers ch wloerriede se spoaluratitoend a anndd} p ^b _{ressure. The residue was purifi} ^{filtered and the solvent was removed under reduced} _{15 d %ic}

d _th

u_olo

c _3ro

e_{d %me}

p_{r mth}

e_{eathnaen aonl)d. T ah 7eN pr aomdmucotne}

f_irad

a_{c s b}

t_oy

i_{olunt f}

s_iloa

w_nsh

e _{arn c}

e_dol

c_{o mum}

l_leetn

c_{hta c}

e_nh

d_or

a_lo

n _am

d_sa

t _eto

h_leugera

s_np

o_tlshy

v_{e (gnr o}

t_av

w_de

a_{iresn stil}

r_{e eic}

m_lua

o_{tivo g enel d fr u uos nming de 0 re r Yield: 90 mgss oure.}

L_{C f example N47 (69%)}

2_{0 MS method 2: MH+ = 423, RT = 2.369 min E Examp}

a_cxcaoml

r_dpile

n_{e N}

g _N4

t_{o488 the m paryoc beed purreepsa ilrluedstr faotlelodw fionrg th geen pereraplar sacthioenm oef e 1x,a smtaprltein Ng2 f3ro.m example N45 and} -184-

E ^Example

r^e _e ^p _s ^a

a_c ^x _c ^a _o ^m _rd ^p _i ^l _n ^{e N}

g ^N4

t_o ⁴⁹⁹ _the ^m _p ^a _r ^y _oc ^b _e ^e _d ^p _u ^r _il ^r _lu ^ed _str ^f _at ^l _e ^l _{d f} ⁱ _or ^{g g l h 1, starting from example N45 and} 5 _{the preparation of example N23.}

E

E^{xa p}

a_c ^x _c ^am

o^m _rd ^{ple N}

i^l _n ^e _g ^N5

t_o ⁵⁰⁰ _the ^m _p ^a _r ^y _oc ^b _e ^e _d ^p _u ^r _r ^e _e ^p _s ^a _il ^r _lu ^ed _str ^f _a ^o _t ^l _e ^lo _d ^w _f ⁱ _o ⁿ _r ^g _th ^g _e ^en _p ^e _re ^ra _p ^l _ar ^s _a ^c _t ^h _io ^e _n ^m _o ^e _{f e} ¹ _x ^, _a ^s _m ^ta _p ^r _l ^t _e ⁱⁿ _N ^g ₂ ^f ₃ ^ro _. ^{m example N45 and}

^{10 E}

E^xam

i_ll ^x _u ^a _s ^mp

t_ra ^pl

t^le

e^{e N}

d ^N5

f_o ⁵¹

r¹ _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^fo _a ^l _m ^low _pl ⁱ _e ^ng _N2 ^g ₈ ^e _. ⁿ _T ^e _h ^ra _e ^l _p ^s _r ^c _o ^h _d ^e _u ^m _ct ^e _w ¹ _as ^an _o ^d _bta ^a _i ^c _n ^c _e ^o _d ^rd _a ⁱⁿ _s ^g _th ^t _e ^o _H ^th _C ^e _{l s} ^p _a ^r _l ^o _t. ^cedures -185-

E^xamp

E^{x N52}

P_re ^a _p ^m _a ^ple

r_a ^le _tio ^N _n ⁵² _of ^m _in ^a _te ^y _r ^b _m ^e _e ^p _d ^r _ia ^e _t ^p _e ^a ₉ ^re ₃ ^{d following general scheme 1.}

^{5 33-8b2r.o8m0o m-6m-cohl)lo wroe-riem siduaszpoe[n1d,2e-db] ipny nri-dbaut}

^{i (l8 (19104. g8438l2)8 i am porle)s asnudre 2 t-aminoethanol (23.15 ml, for 20 hours. The reaction mixture was cool ube and heated at150°C} p_{ressure. The mixture} ^{ed and the volume was reduced under reduced} _{10 1 was triturated with ethyl acetate. The solids were filtered off a}

Y_{i heo}

M_ldu

S_{:r 7 u}

m_.5n

e_0de

t_{h gr reduced pressure at 70°C. nd dried for LC o odf 2 in:t MerHm+e =di 2a5te8, 9 R3T (7 =6% 1.2)23 min}

P_{reparation of intermediate 94}

^{15 I Nn,tNer-mdiemdeiathteylf 93 (5.0 g, 19.45 mmol)}

^{d tithyl i (4055 ml, 29.17 mmol) were dissolved in atmosph ormamide (150 ml). Th ti it as cooled to 0°C under nitrogen} d _{teicmhploerroam} ^e

t_ue ^re

r_{eth fa} ^a

o_n ⁿ

r_e ^d

2 ₍ ^a

h_2o0 ^so

u_{rs m} ^lu

._{l T)} ^tio

h _w ⁿ

e_{a rs} ^of

e_{a acd} ^m

t_id ^e

o_e ^t

n_d ^hyl

m_{i d} ^s

x_r ^u

t_o ^l

u_p ^fo

r_ew ⁿ _i ^y

w_s ^l _ea. ^m

s _{p T} ^e

o_h ^th

u_e ^an

r_{e rde} ^e _a ^{sulfonate (4.41 g, 25.29 mmol) in} _{20 sclotiwonly i mntioxt wuraete wr (a6s00 st mirrl)e.d Th aet s rooloidms} ^{w dreiered f uilntedreerd v oafcfu aunmd. t Tohlueen coem wpaosu anddd weads a unsde r - de1m86}

w^{io- thvoeudt u funrdtheer reduced pressure. The solids were} Y_ield ^{r purification in the next step.}

L_{CMS: 6 m.2e9 g of intermediate 94 (96%)}

5 _{thod 2: MH+ = 336, RT = 1.767 min}

P_{reparation of intermediate 95}

[ ^{d(i2sSso)-lpvyerdro ilnidi dni-c2h-lyolr]mometehtahnaonel (2 (7.540.16 g,}

^{2l4).72d ll)d td i 0Cida uznodleer (2 n.i5tr2og ge,n 3 a7t.m08os mpmheorle). w teerrte 10 b}

a ^stu

n^irt

d^ryel(

w^dch

a ^al

s^to

h ^rr

e^oo

d^o)dmip

w^{i th}

t^ee

h^mn

a^py

n^els

a^riala

q^tuun

e^{ree (}

o^{u f7o.}

s^r1

1¹¹

N^{68 h g}

h^o,

y^{durr 2}

o^s7..

c^{h T1}

l^h9

o^{e m remaoclt)io wna msix atudrdee wda asn ddilu thteed r weaithcti doinch mlorixotmureeth wanaes-}

b_{icarbonate solution. The} ^{ric acid solution and an aqueous saturated sodium} 5 _{reduced pressure. The re osirdguaenic wa lasye pru wrifaiesd dr bieyd f,la fislther ceodlu amnnd t chhero smolavteongtra wpahsy re omveorve sidlic under 1 u frs m}

e_oi

m_mng

o_{v 0 di}

e_{d %chlo}

u_{n toro}

d _{6e %tha onfe m aentdha ano 7l)N. T ahmem pornoidau scotlu frtaiocntio inns m weethrean coolll aescte edlue anntds t (hgerad sioelnvten etlau wt gioe anl r s Y e}

C_{ieMldS: 8 m.0e0th go or}

d_{f 2 i rneduced pressure.}

L _{:t MerHm+e =di 3a4te095 (95%)}

2_{0 Preparation of intermediate 96}

^{A ca mrbioxntuartee o (f2 intermediate 94 (3.10 g, 9.25 mm -1o8l)7,- intermediate 95 (1.20 g, 11.10 mmol), sodium sulfoxide (27..79541 m gl), w 2a7s.75 sti mrremdol a)t a 6n0dºC potassium iodide (1.997 g, 12.03 mmol) in dimethyl 5 water (350 ml) and extracted with ethyl ace fotarte 1.6 Th heou crosm. Tbihneed re oarction mixture was poured into b pruinriefie,d dr bieyd f,la fsilhte creodlum annd ch threom saotlvoegnratp whays ov reemr soved under reducegdan picre lsasyuerres. w Tehree w reassidhueed w wiaths eluents ilica gel using dichloromethane and methanol as} t_{he solv} ⁽ _e ^g _n ^r _t ^a _w ^di _a ^e _s ^nt _re ^e _m ^lut _o ^io _v ⁿ _ed ^fro _u ^m _nd ^{0 % to 5 % of methanol). The product fractions were collected and} _{10 column chromatography overe sril riecadu gceeld u psriensgsu hreep.ta The residue was purified by a second flash e (gluratidoinen frto emlu 0tio %n t foro 8m00 % % of to eth 4y %l ac oefta mtee) and usingn deic ahnlodro emtheythla anceet aanted a mset ehluaennotls as (g eraludeienntst so thanol). The product fractions were collected and the Yielvlde:nt 2 w.0a0s g re omf ioved uendder reduced pressure. 15 LCMS method 2:n MteHrm+ = 5ia7t9e, 9 R6T ( =373%.0)81 min}

P_{reparation of intermediate 97}

4

2^{0 9-6(D (1im.9e0th gy,l 3 a.m28in mo)mpyorli)d ainned (0 di.-2t0t g-,b 1t.y6l4 di bl) t (1d.0d7d t a stirred solut tieotnra ohfy idn thle). rtoefrumraendi (a1t5e m s Tohlvee rneta wctaiosn r memix g, 4.92 mmol) in}

o^{tuvreed w uansde strir rreeddu acte 6d5 p°C for 4 hours. The reaction mixture was cooled and} c_{hlurtoiomna ftroogmra 0ph %y t oov 4er % si olifc mae gthealn uosl)in.g Th deic ph} ^re

r_l ^e

o_o ^s

d_r ^s _o ^u

u_m ^r

c_te ^.

f_trh ^T

a_a ^h

c_n ^e

t_ioe ^re

n_{s a} ^s _n ⁱ

w_d ^du

e_{r m} ^e

e_e ^w

c_toh ^{as purified by flash column} e _{llaencoteld a asnd elu theent ssolv (gernatdient 25 removed under reduced pr was Y LCieMldS: 2 m.1e5th god of 2 i:n Mte essure.}

H_{rm+e =d 6ia7t9e, 9 R7T ( =973%.6)23 min} ^-188- P_{reparation of intermediate 98}

5 ^Iyn

m^l)t

i^pe

x^thrm

u^erne

e^od

o^lia

f ^(t

1^{1e 5}

,^.40-67

d^{io gx, (2}

a ^4.45

n^.1

e^{4 an m g,}

d^{m 7}

w^o8

a^l).2

t^{e a0}

r^{n (3d:1 p, 9tl),}

.^{51i 4fl (4,}

m^{l). p Th3}

h^{e rpehact4,5}

t^{ion t,5i mbt}

i^xstr

t^iucam

r ^{(3et ehqyl.-)1 w,3e,2re-di doixssaoblovreodla inn-2 a- nitrogen gas through the mixture.2-Dicyclohexylphosphino-2 e was degassed by bubbling (153 mg, 0.32 mmol) and tetrakis(triphenylphos ’,4’,6’-triisopropylbiphenyl (Xphos) added and the mixture was stirred under nitrophine)palladium(0) (186 mg, 0.16 mmol) were} _{10 m anix}

r_edtu

s_{s br}

u_{rei as}

r_{n w}

e_{e.. T Thh c}

e_eoo

r _ole

e_rsgd

i_a.

d_{n D}

u_{iecich l walo}

a_yreo

s_rm

p _we

u_ath

r_isa

f_{ie dn}

d_{reie w}

b_{dy,as f fill a}

a_ted

s_rd

h_eedd ^ge _a ⁿ _nd ^g _t ^a _h ^s _{e o} ^a _r ^t _g ⁸ _a ⁵ _n ^° _ic ^C _la ^f _y ^o _e ^r _r ¹ _w ⁶ _as ^ho _w ^u _a ^rs _s ^. _he ^T _d ^he _wit ^r _h ^ea _w ^c _a ^ti _t ^o _e ⁿ _{r p co alnd the solvent was removed under reduced dichloromethane and methanol as eluents (96,5: umn chromatography over silica gel using the solvent was removed under reduced pres 3,5). The product fractions were collected and 15 Y LCieMldS: 1 m.7e6th go odf 2 in:t MerHm+e =di 7a1te0, 9 R8T (7 =8% 3.5) sure.}

2_{0 min}

P_{reparation of intermediate 99}

^{20 A un sdoelrut nioitnro ogfe innte artmmoesdpiahteere 98. T (1}

^{.t71b g,ty 2l.41 il) i fl ttidhyd (1Mf lut (i7o.n23 in m tel)tr waahsyd crooofuleradn t,o 0°C} m_{mlvoeln)t w waass a rdedmeodv.e Tdh uen rdeearc rteiodnuc meidxtu prrees wsuarse s atnirdred the at re rosoidmue te wmapse drailtuutreed f worith 20 eth hoylur asc.} ³ e _T ^.6 t_ah ¹ s_{o tee} ^{a dnrided w,a filstehreedd w ainthd a thne a sqoulveeonuts w saastu rreamteodve sdod - ui1}

n^u8

d^{m9- er b riceadrubcoendat pere ssosluurtieo.n T.h Tehe res oirdguaenic layer was by flash column chromatography over silica gel using dichloromethane and was purified} e_{luents. The product fractions were collected and the solvent was removed u} ^{methanol as} 5 _{p Yr}

L_Ciees

M_lds

S_{:u 8re. nder reduced m40et mhogd o 2f: in MteHr+m =ed 4i7a2te, R 9T9 ( =742%.06)8 min}

P_{reparation of intermediate 100}

^{10 A de sgoalsustieodn of by inte brmubebdliinagte 9 n9itr (o4g40}

^{g g, 0.93 th glh) i th 2 thiytlttr.ah Aydro sfouran (20 ml/mmol) was azodicarboxylate (550 mg, 2.79 mmol) in anhydrous toluene (20 ml lution of diisopropyl 15 bubbling nitrogen gas through the mixture. Both solutions were a/mmol) was degassed by d mrgo,pw 2.i7s9e m ovmerol a) i pne arinohdyd orfo 2us ho toulrusen aet 9 (07°5C m tlo/m am doel)g.a Tshseed re saoclution odfd treipdhe sinmyulplthaonsepohuinsely ( a7n3d2} s_{ohlrvoemnatto wgarsap rheymo ovveedr s uilnicdaer g reeld uusciendg p driecshslourroem.e Tthhean rees aidnude} ^tio _w ⁿ _a ^m _s ^ix _p ^t _u ^u _r ^r _i ^e _fie ^w _d ^as _by ^co _f ^o _la ^le _s ^d _h ^a _c ⁿ _o ^d _lu ^t _m ^he c _{n 0 elution from 0 % to 4 % of methanol). The product fractions r mee ctohllaencoteld a asnd el tuheent ssolv (gernatd wieanst 2 r Ye}

C_imeMldo

S_{:ve 5 m9d0 un we et md}

h_oger

d _{o 2f re}

: _{induced pressure.}

L _{MteHr+m =ed 4i5a3te, R 1T00 = (720.2%93) min}

P_{reparation of example N52}

25

^{Intermediate 100 (590 mg, 0.65 mmol) was -1 d90- m issolved in a 4N hydrochloric acid solution in coeotlheadn,o sl (4 ml). The reaction mixture was stirred at 50°C for 16 hours. The reaction was 5 room temlpoewrly poured into an aqueous saturated sodium bicarbonate solution and stirred at c poremsbsiunreed. T ohragt}

e^{aunre for 30 minutes. The aqueous layer was extracted with dichloromethane. The reicsid layers were dried, filtered and the solvent was removed under reduced dichloromethane andue a 7 wNas a purified by flash column chromatography over silica gel using} % _{to 4 % methanol). The pro} ^m _d ^m _uc ^o _t ^{nia solution and methanol as eluents (gradient elution from 0} r_{educed pressure. The residue wa fsra fctions were collected and the solvent was removed under 10 ( rHedPuLcCed m perethsosd}

o_{ufr Ae). The product fractuiortnhser w peurreifi ceodll beycte redve arnsded th peha ssoelve cnotlu wmans c rhermomovaetodg uranpdheyr Y LCieMldS: 2 m9e mthgod 2 e:x.}

M_{amH+pl =e 3 N5532, R (6T% =) 1.398 min}

1_{5 E Ex le}

i_llxa

u_ammp

s_{traptlee N}

d _N5

f_o53

r_{3 th mea pyre bpear parteiopnar oefd ex foalmlowplieng N4 g5e.n Tehrael p srcohdeumcte w 1as an odbta aicnceodrd aisng th teo H thCel s parlot.cedures}

^{20 E Exam e N}

e_x ^x _a ^a _m ^mp

p^pl

l^l _e ^e _N ^N5

5⁵⁴

3⁴ _. ⁱ _T ^s _h ^o _e ^b _p ^ta _ro ⁱⁿ _d ^e _u ^d _ct ^a _w ^s _a ^a _s ^s _o ^id _bta ^-p _ined ^d _as ^t _t ^d _he ⁱ _HC ^g _l ^th _salt ^M _. ^{it bu reaction in the preparation of}

^{E Exa ple}

2_{5 ill} ^x _u ^am

s^m _tra ^p _t ^l _e ^{e N}

d ^N5

f_o ⁵⁵

r⁵ _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^fo _a ^l _m ^low _pl ⁱ _e ^ng _N4 ^g ₅ ^e _. ⁿ _T ^e _h ^ra _e ^l _p ^s _r ^c _o ^h _d ^e _u ^m _ct ^e _w ¹ _as ^an _o ^d _bta ^a _i ^c _n ^c _e ^o _d ^rd _a ⁱⁿ _s ^g _th ^t _e ^o _H ^th _C ^e _{l s} ^p _a ^r _l ^o _t. ^cedures -191-

E^xamp

i ^E _ll ^x _u ^a _s ^m _tra ^ple

t^l _e ^{e N}

d ^N5

f_o ⁵⁶

r⁶ _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^f _a ^l _m ^l _pl ⁱ _e ^g _N1 ^g _1. ^{l h 1 and according to the procedures}

^{5 E}

E^{xa pl}

P^x _re ^am

p^{m e N5}

a^p _ra ^le _tio ^N _n ⁵⁷

o⁷ _f ^m _in ^a _te ^y _r ^b _m ^e _e ^p _d ^r _ia ^e _t ^p _e ^a ₁ ^re ₀ ^d ₁ ^{following general scheme 2.}

^{10 A chl morioxt-upryera ozfol toe[r1t-,5b-uaty]ply (r3imS)id-3in-aem (3in.4o8p}

^{i gp, 1i4d.i981 lb) ydl Nte,N (-2d.i0is0op gr,o 9p.y9le9th mylmamoli)n,e 3 (-2b.r6omo-5- 14.98 mmol) in acetonitrile (30 ml) was stirred at 90°C for 24 ho 16 ml, pyhreaz reoaloc[t1io,5n-a m]pixytruimreid winaes ( c0o.5ol eeqd.) a w urs. More 3-bromo-5-chloro- T ndas th aedd seodlve anntd w thaes m reixmtuorveed wa usnd setirrre redd autce 9d0° pCre fosrsu 2r2 hours.} _{15 a filcteertaetde a wnads th aedd soeldve annt w thaes o rregmaonviced lay uenr was washed with water. The organic layer wa} ^e _s ^. _d ^E _ri ^t _e ^h _d ^y _, ^l c_{orlaumn chromatography over silica gdeelr u residnugce ddic phrleosrsoumree.th Tahnee re asniddue m weathsa pnuorlifi aesd b eylu felash (gvdeinetn wta eslu rteiomno fvroemd u 0nd %er t roed 8u %ced of pr meessthuaren.ol). The product fractions were collected and tnhtes sol} ^{LCMS method 2: MH+ = 397, RT = 4.609 min -192-} P_{reparation of intermediate 102}

5 ^{I mnteetrhmaneodlia (te 101 (4.08 g, 10.30 m}

^{l) ti d i 4N hydrochloric acid solution in nitrogen ga3s0 w mal)s a btu rboom temperat f 4 h . Mthnol and toluene were added and} p_{ressure. Toluen} ^{bled through the mixture. The solvent was removed under reduced} _{10 was used w e was added twice and removed twice under reduced pressure. The product LCMS methiothdo 2u:t M fuHrt+he =r 2 p9u7r,ifi RcaTti =on 1. i4n1 t8he m ninext step. Preparation of intermediate 103}

^{15 2 i}

^{, 5.}

m^n-tb

g^er

,^romm

4^.eo

8^de

6^iath

m^teox

m ^1y

o^{0- l)2tert}

i^{n (4- N.b8u}

,^N6ty

-^{d ml-dmimole),th tryiel-tshilyl i (1.2 (425.027l l,8314 m.5m8o ml)m woal)s a anddde pdota toss aiu smus iopdeindseio (n80 o7f 16 hours imethylacetamide (6.7 ml). The reaction mixture was stirred at 80°C for} w_{ashed w} ^{. T} _ith ^he _w ^r _a ^e _t ^a _e ^c _r. ^tio _T ⁿ _he ^m _o ^ix _r ^t _g ^u _a ^re _ni ^w _c ^a _la ^s _y ^c _e ^o _r ^o _w ^le _a ^d _s ^{, e} _d ^t _r ^h _ie ^y _d ^l _, ^a _f ^c _il ^e _te ^ta _re ^te _d ^w _a ^a _n ^s _d ^a _th ^dd _e ^e _s ^d _o ^a _lv ⁿ _e ^d _nt ^th _w ^e _a ^o _s ^rg _re ^a _m ^{nic layer was} _{20 reduced pressure. The residue was pur eified by flash column chromatog oved under u Tshieng}

M _{pSr doi}

m_dch

e_ul

t_co

h_tr

o _fo

d_{rma 2ce}

:_titoh

M_na

H_sne

+ _{w a}

=_en

4_red

5_{5 c m}

,_{o Rleleth}

T_{cat =endol}

2_{. a a}

3_ns

7_{d7 t mhlueents (gradient elution from 0 %ra toph 8y % ov oefr m seitlihcaano gle).l LC in solvent was removed under reduced pressure. Preparation of intermediate 104} ^-193-

^{D (1i.-9te2r5t-b gu,ty 4l.2 d4ica mrbmonoal),te tr (i1e.th11yl1}

^{gi, 5.0 (90. l) ddd to a mixture of intermediate 103 5 ( 20. h2o5u9rs g., M 2.o12 mmol) in tetrahydrofuran (1828.472 ml,l).6. T3h6e reacotli)on an mdix 4tu-r(edim waesth sytlirr aemdin aot) 7p0y°rCidi fnoer mixture wasr setir drei-dte artt-b 7u0t°yCl d foicra 1rb6o hnoauters (.1 M.2or eeq d.)i- atenrdt-b turiteytlh dyilcaamrbinoena (0t.4 eq.) were added and amino)pyridine (0.3 eq.) were added and mixture was s e (3 eq.) and 4-(dimethyl} 0 ^{crude reaction mixture was purified and t tirred again at 70°C for 20 hours. The} _{1 d 7i0c°arbonate (2 eq.) and 4-(dimethyl amino)pyrid} ^h _i ^e _ne ^r ₍ ^e ₀ ^a _.8 ^cti _e ^o _q ⁿ _.). ^w _T ^a _h ^s _{e r} ^r _e ^e _a ⁱⁿ _c ⁱ _t ^t _i ⁱ _o ^a _n ^te _m ^d _ix ^u _tu ^s _r ⁱⁿ _e ^g _wa ^d _s ^i- _s ^te _ti ^r _r ^t _r-_e ^b _d ^ut _a ^y _t ^l r_edinuC

g_{ce fo}

h_dr

e_{p p 1}

t_rae6

n_{ses huo}

a_ru

n_er

d_.s.

e _{Tth T}

h_ehe

y_{l r ae r}

c_se

e_ida

t_auct

t_eio

e _{a wn}

s_{a msix}

e_{lu pt}

e_uu

n_rrie

t_{fsie w}

(_da

g_{r bs}

a_{y c}

d_{ie folnao}

t_slhed

e_{lu cto a}

i_olnud

n_{mn th cehr soomlvaetnotgr waapshy re omveorve sdilic uand geer us l The product fractions were collected and the s fromd 0 u %nde tor 5 re0d %uce odf e ptrheysls aucreet.ate). 15 Y LCieMldS: 1 m.2e4th9o gd o 2f: i MntHe+rm =e 5d5ia5t,e R 1T04 olvent was remove}

= _{( 35.32%85) min}

P_{reparation of intermediate 105}

^{A thr mouixgthure the of m 1i,x4t-udrieoxane and water (3:1, 1 -21.094 m-l) was degassed by bubbling nitrogen gas 1,3,2-dioxaborolan-2.-y Iln)ptehremneodiate 104 (1.149 g, 2.07 mmol), 4-fluoro-3-(4,4,5,5-tetramethyl- 5 (46 mg, 0.04 mmol), 2-dicyclolhe (0x.y5lp9ho gs,p 2h.i48 mmol), tetrakis(triphenylphosphine)palladium(0) m stimrroeld) u anndde pro ntaitrsosgiuemn g pahsos apth 8a5te°C tri fboars 1ic4 (n}

h^1o

o^.3-2

u^1’

r^8,4’

s^{. g,6}

T^{,’- h 3trii}

e ^es

r^eqo

a^{.p)ropylbiphenyl (Xphos) (38 mg, 0.08 ct wioenre m aixdtudreed w aansd c thoeole mdix ature was} a_{cetate was added. The organic layer washed wit} ^{nd ethyl} r_{emoved unde h water, dried, filtered and the solvent was 10 over silica gelr u rseindguc heedpt parneess aunred. e Tthe residue was purified by flash column chromatography e rethdyulce adcetate). The product fractionhsyl w aecreeta cteoll aescte edlue anntds ( tgradient elution fr}

s_{u as roemmo 0v%ed to un 80d% p er LCMS mer he solvent w}

t_{heosd 2re:. MH+ = 586, RT = 3.335 min}

P_{reparation of intermediate 106}

^{15 T ae stroalubtuiotynla omfm inotenriummed fliuaoride (1M}

^{lti i tt hyd f , 2.48 ml, 2.48 mmol) was added to was stirred at room temtpee 1ra0t5ure (2. f0o7r 17 holu)r is. t Thteh myidxtufre w (6.21 ml). The reaction mixture 0 washed with water and a saturated aqueous sodium bicarboansat deilu stoelduti wonith. T ehtheyl o argcetate and 2 w} _pu ^a _r ^s _ifie ^d _d ^rie _b ^d _y ^{, filtered and the solvent was removed under reduced pressure. The resaidnuice la wyaesr} e_{hluee snotslve (gnrta fl}

w_dais

a_eh

s_{nt c}

r_{e eo}

m_lluu

o_tmivon

e_{n c}

d _{frhromatography over silica gel using dichloromethane and methanol as t uonmde 0r % red touc 8e %d p orfe msseutrhanol). The product fractions were collected and 25 Yield: 844 mg of inteHr+m =ed 4i e.}

L_{CMS method 2: M 7a2te, R 1T06 = (826.3%51) min}

P_{reparation of intermediate 107} -195-

A ^{wa ssolu dteiognas osfe idnte brymediate 106 (7}

^{44 g 158 l) i 2 thyltetrahydrofuran (20 ml/mmol) azodicarboxylate (1.5 b6u6bb mlinl,g 7.9 n0it mgmol) g in an thhydgh th itre. A solution of diisopropyl 5 b durobpbwlinisge n ovitreorg aen pe griaosd o thfr 2ou hgohurs th aet 1 m1i0xt°uCre t.o B ao dtehrou}

g^{a ssosslu to}

e^tdiloune

s^osne

l^{u w (}

t^{ie20 ml/mmol) was degassed by orne o afd trdipehden simultaneously and g, 7.90 mmol) in anhydrous toluene (75 ml/mmol). The reaction mixture wasy sltpirhreodsphine (2.072} 3_{0 minutes. The mixture was cooled and t} ^{at 110°C for} r _{he solvent was removed under reduced pressure. The 10 ee}

f_{rtahsi acyd stlu}

i _{to ae rinc was purified by flash column chromatography over silica gel using dichloromethane and tuset}

r_{a wa}

t_eete

d_{re a}

w _cs

i_{tohl eleluents (gradient elution from 0 % to 50 % of ethyl ac actee etate). The product w ctodn aitnridl the solvent was removed under reduced pressure. The residue Yield: 678 mg of int e, the solid was removed and dried under reduced pressure.}

L_{CMS m ermediate 107 (95%)}

1_{5 ethod 2: MH+ = 454, RT = 2.365 min}

P_{reparation of example N57}

I

0 ^mnt

m^{eetrhmaneodlia (t4e.41707 ml) (6 a7t8 ro mogm, t 1e.m49peraturel) for 4 htoiursd a ind at 45N0 h ºCydr foocrh 2lo hriocur asc.id Th solution in 2 n} e _ni ^{ixture was stirred at room temperature for another 14 hours. Diethyl ether was aedd reeadc ationd} t_thro

d_eg

u_re

c_{e an}

d_{nd gas was bubbled through the mixture until the diethyl ether was evaporated. Diethyl re pre ass feuwre. d Trohpes pr oofd muethanol were added and the solid was filtered and dried under Y LCieMldS: 2 m19et mhogd o 2f: e MxaHm ct was obtained as the HCl salt.}

2_{5 +p =le 35 N45,7 R (T38 =% 2).056 min} ^{Examp -196- E} _ex ^x _a ^a _m ^m _p ^ple

l^l _e ^{e N}

N ^N5

5⁵⁸

5⁸ _. ⁱ _T ^s _h ^o _e ^b _p ^ta _ro ⁱⁿ _d ^e _u ^d _ct ^a _w ^s _a ^a _s ^s _o ^id _b ^e _ta ^-p _in ^r _e ^o _d ^du _a ^c _s ^t _t ^d _h ^u _e ^ri _H ⁿ _C ^g _l ^th _sa ^e _lt ^M _. ^{itsunobu reaction in the preparation of}

^{5 E Example N59}

e_x ^x _a ^a _m ^m _p ^p _l ^l _e ^e _N ^N ₅ ⁵ ₂ ⁹ _. ⁱ _T ^s _h ^o _e ^b _p ^ta _ro ⁱⁿ _d ^e _u ^d _ct ^a _w ^s _a ^a _s ^s _o ^id _bta ^-p _ined ^d _as ^t _t ^d _he ⁱ _HC ^g _l ^th _salt ^M _. ^{it bu reaction in the preparation of}

1^{0 E Ex le}

i_ll ^xa

u^amp

s^m _tra ^p _t ^l _e ^{e N}

d ^N6

f_o ⁶⁰

r⁰ _th ^m _e ^a _p ^y _re ^b _p ^e _ar ^p _a ^r _t ^e _io ^p _n ^ar _o ^e _f ^d _ex ^fo _a ^l _m ^low _pl ⁱ _e ^ng _N5 ^g ₇ ^e _. ⁿ _T ^e _h ^ra _e ^l _p ^s _r ^c _o ^h _d ^e _u ^m _ct ^e _w ² _as ^an _o ^d _bta ^a _i ^c _n ^c _e ^o _d ^rd _a ⁱⁿ _s ^g _th ^t _e ^o _H ^th _C ^e _{l s} ^p _a ^r _l ^o _t. ^cedures

^{E Examp}

a^{xampllee N}

1₅ ^{N6611 may be prepare}

o_{cbctaoirndeindg as to th tehe H pCrlo scaeldt.ures ill} ^d _us ^f _t ^o _ra ^ll _t ^o _e ^w _d ⁱⁿ _f ^g _or ^g _t ^e _h ⁿ _e ^e _p ^ra _re ^l _p ^s _a ^c _r ^h _a ^e _ti ^m _on ^e _o ² _f ^, _e ^s _x ^ta _a ^r _m ^tin _p ^g _le ^fr _N ^o ₁ ^m _1. ^e _T ^xa _h ^m _e ^p _p ^l _r ^e _od ^N _u ⁶ _c ⁰ _{t w} ^an _a ^d _s -197-

E

E^xampl

a_c ^x _c ^a _o ^m _rd ^p _i ^le

n^{e N}

g ^N6

t_o ⁶²² _the ^m _p ^a _r ^y _oc ^b _e ^e _d ^p _u ^r _r ^e _e ^p _s ^a _il ^r _lu ^ed _str ^f _a ^o _t ^l _e ^lo _d ^w _f ⁱ _o ⁿ _r ^g _th ^g _e ^en _p ^e _re ^ra _p ^l _ar ^s _a ^c _t ^h _io ^e _n ^m _o ^e _{f e} ¹ _x ^, _a ^s _m ^ta _p ^r _l ^t _e ⁱⁿ _N ^g ₄ ^f ₇ ^ro _. ^{m example N55 and}

^{5 E}

E^xaml

e_xxaamm ^p

p_pll ^{e N}

e_{e N N} ⁶

6₆ ³

2_{3. is obtained as a side-product during the Suzuki reaction in the preparation of}

¹⁰

T_{able 1} -198- _C

_{p d N1 E pl N1 Cp d N2 E pl N2 C}

_{p d N3 E pl N3 Compound N4, Example N4}

_{Cp d N5 E pl N5 Cp d N6 E pl N6 C}

_{p d N7 E pl N7 Cp d N8 E pl N8} -199- C_{p d N9 E pl N9 Cp d N10 E pl N10 Cp d N11 E pl N11 Cp d N12 E pl N12 Cp d N13 E pl N13 Cp d N14 E pl N14 Cp d N15 E pl N15 Cp d N16 E pl N16}

-200- _C

_{p d N17 E pl N17 Compound N18, Example N18 C}

_{p d N19 E pl N19 Cp d N20 E pl N20 C}

_{p d N21, E pl N21 Cp d N22, E pl N22 C}

_{p d N23 E pl N23 Cp d N24 E pl N24} -201- _C

_{p d N25 E pl N25 Cp d N26 E pl N26 C}

_{p d N27 E pl N27 Cp d N28 E pl N28 Compound N29, Example N29 C}

_{p d N30, E pl N30 Compound N31, Example N31 Compo}

_{d N32 E ple N32} -202- _Com

_{p d N33 E pl N33 Cp d N34 E pl N34 Co}

_{p d N35 E pl N35 Cp d N36 E pl N36 Compound N37, Example N37 Co}

_{p d N38, E pl N38 Co}

_{p d N39 E pl N39 Compound N40, Example N40} -203- _{Compound N41, Example N41 C}

_{p d N42 E pl N42 Com}

_{p d N43 E pl N43 Cp d N44 E pl N44 C}

_{p d N45 E pl N45 Cp d N46 E pl N46 C}

_{p d N47 E pl N47 Cp d N48 E pl N48} -204- _{Compound N49, Example N49 C}

_{p d N50 E pl N50 Compound N51, Example N51 Co}

_{p d N52, E pl N52 C}

_{p d N53 E pl N53 Compound N54, Example N54 C}

_{p d N55, E pl N55 Cp d N56, E pl N56} -205- C_{p d N57 E pl N57 Cp d N58 E pl N58 Cp d N59 E pl N59 Cp d N60 E pl N60 Cp d N61 E pl N61 Cp d N62 E pl N62} C^{p d N63 E pl N63}

^{Compound identific -206- Meltin ation}

F ^{moerth theg m poeilntintsg point determination of the compounds of the present invention, the following 5 od was used. F M}

M^oe

e^rlt

t^{t ain}

l^{e ng}

r^{u p}

F^mo

P^bin

6^et

2^{r m}

a ^oe

p^ft

p ^ch

a^oo

r^md

a^{tpuosu.n Mdesl,tin mge pltionignt pso winetrse ( mme.pa.s) were determined in open capillary tubes on a 300°C , using a gradient of 10 °C/minute. Theu mreeldtin wgith po ain tetm vpaelureature ranging from 50°C to 10 display and was not corrected. was read from a digital Tab CleO 2: Melting points}

N^M _UM ^PO _B ^U _ER ^{ND MELTIN} _(° ^G _C) ^{POINT CO} _N ^M _UM ^PO _B ^U _ER ^{ND MELTIN} ₍ ^{G POINT}

N_{1 272,3 N3 °C) N2 > 30 6 189,8 N3 N 0 N37 168,1 N4 D* N38 >300 N5 2245 N39 ND* N6 27813,,94 N N4401 N NDD* N7 258,8 N42 * N8 >300 N43 ND* N9 294, 178,1 N10 >35 N44 ND* N11 > 30000 N N4456 118684,1 N12 ND* N47 ,7 N13 > 30 154,6 N14 > 3000 N N4489 113593,,6 N15 ND* N50 1 0 N16 211,5 12,9 N17 >300 N N5512 225866,,89} -207- N ^{N198 275,1 N53 276,8 N1 N220 2 1 288,55 N5 2892, 5,3 N N54 55 2 6 228 2831,5}

^{N22 > 300 N57 >3,3} N_{23 183,2 N58} ³⁰⁰ N_{24 208,3 N59 2 N/A N25 288,6 N6 60,3 N26 >300 N601 >300 N27 199,9 N62 22298,7 N63 2666,,51}

* ^{Not determined 5 L FC}

w^oarM

s ^LS

u^{CseMdS.-characterization of the compounds of the present invention, the following method}

^{A Glene}

1^{0 A degl}

g^{il aenraa ansstlly p e 1s}

r^,2ero

9^{sce a0 wd uto seu}

e^{rere sriae p L mseCr}

p ^{lfM lio}

e^{qrS rum}

,^ided

t^{h c using an Agilent 6110 series LC/MSD quadrupole coupled to an ehrmroomsatatotegdra cpohlyum (LnC c)o smypsatertmme cnotn asinsdtin dgio odfe a ar brainyary pump with} m_{ass spectrometer (MS) was operated with an atmosphe} ^{detector. The} ( _{vAoPltaI-gEeS t)o s 7o0ur Vce a innd p tohseit qivue ric pressure electro-spray ionization ad iornup mooled tee.m Tpheera ctaupreilla wrays vo mltaaignetai wnaesd s aett 1 t0o0° 3C0.00 V, the fragmentor 15 a nn}

C_ed

h_{beu tzm}

m_leistearpe

t_{io gra}

n_atsu

s_,re

o_{ft awt va}

a_{r alue}

e_{. psre wsesruere 12 o.0f L 3/5mi pns aign.d D 3a5t0a°C ac rqeuspiseitciotinvel wy.as Nit proegrfe T}

o_nh

r_{m we}

e_{a d}

d_sry

w _{uinsg itehd ga A as gs fl to ilehw net}

₂₀ ^LCM

K^{in aedS -208- In tedxi mti Coentho}

1^{8 tod}

c^{o t 1}

l^{huemn ge (n5e0r malm pr looncegd xu 2re.1 L mCmMS i.d1.:; A 1.n7a µlymse psar wtiecrlees) ca artr 6ie0d°C o,ut on a Phenomenex 5 mL/min. A gradient elution was performed from 90% (water + 0.1% w fioth a flow rate of 1.5 A mcoebtiolenit prhileas teo c 1o0m%p (owsaittioenr + w 0a.s1% hel fdor fmoric a anci add)d /it 9io0n%al a 0c.e4t0on mitirnile in 1.50 minurmteisc, t ahceind) th /e 1 fi0n%al was 2 µL. Acquisition ranges were set to 254 nm for the UV . The standard injection volume the MS detector. -PDA detector and 80-800 m/z for 10 L}

A ^InC

Q ^aMdS

C^{d1i mt8ioe}

c^nth

o ^to

l^od

u^{m th 2}

n^{e ( g5e0n mermal p lornogcedure LCMS1: Analyses were carried out on a YMC pack ODS-} m_{L/min. A gradient elution w} ^{x 4.6 mm i.d.; 3 µm particles) at 35°C, with a flow rate of 2.6} A_{cetonitrile to 5% (water + 0.1%as fo prerformed from 95% (water + 0.1% formic acid) / 5% 15 m waosbil 2e µ pLh.a Asecq cuoismitpioosition was heldm foicr a ancid a)d /di 9ti5o%nal A 1c.e0t0on mitriinle. T inhe 4. s8t0an mdianrudte ins,je tchteionn th veolu fimnael m/z for the MS detecntor r.anges were set to 190-400nm for the UV-PDA detector and 100-1400}

_{20 Table 3: LCMS data}

C_{O NMUMPOBUERND MA PSESA (MKH)+ R TEIMTEEN (mTIiOnN) M LECTMHS}

N_{1 336,2 2OD}

_{N N2 3 2,127 2 N3 35533,,01 11,952 2 N4 N5 353,1 1,,90597 573,,0 1,8850 2 6 336 2 N7 354,22 11,,58277 2 N8 354,1 3 2 N9 35 2,098 2 N10 3647,,12 12,977 2 N11 368,1 2,,112174 22} -209- ^{N N1123 33762,2 2,140 2 N14 8,2 1,987 2 N1 368,2 2,040 2 N156 336687,,22 22,,007437 2 N17 368,2 2,1 2 N18 368,2 2,47 2 N19 382,2 220 2 N20 369, 2,193 2 N21 352 1,987 2 N22 374,2 1,96 2 N23 0,2 2,113 2 N2 383,0 2,061 2 N245 339874,,11 22,,152372 2} _{N26 388,1 2,2} ² _{N27 409,2 250 2 N28 369, ,147 2 N29 4230 1,996 2 N30 4,2 2,307 2 N 42,2 ,20 2 N31 09,2 2,08 32 4132 22,36}

N_{3 1, 475 22 N334 335648,,12 21,,0922 2 N35 369,1 870 2 N36 383, 1,885 2 N37 352 2,033 2 N38 43,1 2,061 2 N39 30792,,22 22,,0028700 22} ^{-210- N N41 3368 N40 42 4626, 3,21 22,,0160 ,2120 22 N N43 2 44 44029,1 3,,1 2,210716 22 N45 383,11 2,272 2 N446 7 22,,0192 2 N N47 439 8 42234,,09 22,690 2 ,35 24 2 N49 437,0 2,3515 2 N5501 441101,,50 12,,93719 2 N 2} N_{52 3} ² N _{53,40 1,398 2 N53 382,44 2,004 2 N54 382,44 2,073 2 N55 396,47 2,181 2 N556 24 57 4 8 353,,5430 22,,208526 2 N 2 N659 3 0 39667,,4473 21,,149313 2 N 2 N61 333593,,3480 11,,992747 2 N 2 N6623 443366,,5544 22,,442128 22} ^{5 Kinase Activity Assay}

T _{pehpeti idneh-ibbaitisoend o kfin LaRsReK a2ss kaiyn.ase was assessed using LRRK2 recombinant protein in an in vitro} ^{Prot -211- A kin raao}

s^dc

e^ioo

a^ml

c^{etitvriitcy. p Arollte aisnsa kyinsa asere a psesrafoyrm (3e3Pda innQ 9i6n-awseel®l F AlactsivhiPtyla Atesssay) is used for measuring the reaction volume. The reaction cocktail is pipetted in 4 ste TM from Perkin Elmer in a 50 µl 5 1205 µ µll o off n aossna-ryad bioactive ATP solution (in H2O) ps in the following order: 5 µl of test samuffer/ [γ-33P]-ATP mixture}

1^{0 µl of enzymep/lseu ibns 1tr0a%te D mMixStuOre}

1^{0 T Nhae- assay for LRRK2 contains 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 µM 100o5rt chpomva pneard waetell,), 1 p.2ro mteMin k DinTaTs,e 5 L0R µRgK/m2l ( P7,E3G n2M0)0 a0n0d, A suTbPst (r0a.t3e µ (GMS),K [3γ(-1334P-]2-7A)T,P 1,0 (a µpgp/r5o0x. µ 4l) x The kinase is obtained from Invitrogen Corporation. .} _{15 T 50he µl re oafc 2tio %n ( cvo/vc)kt Hai3lPsO w4e,r pela incubated at 30° C for 60 minutes. The reaction was stopped with NaCl. Incorporation of 33P tes were aspirated and washed two times with 200 µl 0.9 % (w/v) counter. i (counting of“cpm”) was determined with a microplate scintillation 20 Compounds}

T _{bahteh c soomnipcoautonrd.s are dissolved to 10 mM in DMSO. Where needed, solutions are sonicated in a 25 T thaeb alebo 2v pero mveidnetison theed p kIinCa50se va alsuseasy o.f the compounds according to the invention, obtained using Table 4}

C_{omp No1und N° IC50 fo +r+ L+RRK2 Comp No3und N° IC50 for LRRK2 N2 +++ 2 +++ N3 + N33 +++ N4 +++++ N N3345 + +++++} ^{-212- N N56 + +++ N N337}

8 ⁺⁺

+^{++ 6 + ++++ N N7 +++ N +}

N^{38 +++ N9 ++ N3490 + ++}

N^{10 +++ N41 +++ N11 +++ N42 ++++ N12 +++ N43 +++ N13 ++ N44 +++ N N14}

N^{115 +++ N45 + 6 +++++ N N446 + +++++ N + 7 +++ N17 +++ N48 +++} N^{18 +++ N49 +++} N_{129 +++ N50 +++ N20 +++ N51 +++ N21 +++ N52 +++ N22 +++ N53 +++ N234 +++ N54 +++ N25 + +++++ N N5565 + ++++ N N2276 + +++ N57 +++ N28 ++++ N58 +++ N29 +++ N59 +++ N30 +++ N60 +++ N31 ++++ N N61 + +++} ++ indicates an IC50 of between 100 nM and 1µM, an _N62

d₆₃ +++ indicates an I ₊₊

C₊₊ 5₊0 < 100nM

Claims

-213- C^LAIMS

1 _p ^. _redrug, ^A _sa ^c _lt ^o _, ^m _hy ^p _d ^o _r ^u _a ⁿ _te ^d _{, N} ^of _-o ^F _x ^o _id ^r _e ^m _f ^u _o ^la _rm ^I _{, o} ^o _r ^r _s ^a _olv ^s _a ^t _t ^e _e ^re _th ^o _e ^is _r ^o _e ^m _of ^e _, ^{r, tautomer, racemic, metabolite, pro- or}

^{5 Wh}

^I

R^{1e isre}

(^{C sin}

=^{eSle)-cRted from–H,–halo, -OH, -C- lkyl, -O-C- lkyl, -S-C1-6}

4^{, -SO2-R4, -CN, -NR9-SO2-R4, -C3- alkyl, -NR9R10, -(C=O)-R4, - 10 wherein each of said -C 6}

1^{- cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; R5 is su abttsatcithu 6alkyl is optionally and independently substituted with from 1 to 3 eednt tso s Ze1le ocrte Zd5 a frnodm is–h saelloe,ct -eOdR f3r5o,m -N–RH1,1R–1h2a,l -oO,- -CO1H-6,a -lkCy1l-,6a alnkdyl -,S-C1-6alkyl;}

-^{NR6R7, -(C=O)-R8, -(C=S)-R8, -SO2-R8, -CN -O-C1-6alkyl, -S-C1-6alkyl, Ar5 and–Het5; wher , -NR6-SO2-R8, -C3-6cycloalkyl, -O-C3-6cycloalkyl, - from 1 to 3 substitueenitns e saeclehct oefd sa friodm -C–1h-6aallok,y -lO isR o36p,ti -oNnRa2ll3yR a24n,d -O in-dCe1p-6eanlkdently substituted with 15 R2 is o spetiloencatelldy f arnodm in–dHe,p -heanlo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein eayclh, a onfd sa -Sid-C -C1-6}

1^{-a6alklkyyl;l is} O_R27 ^{dently substituted with from 1 to 3 substituents selected from–halo,–} R_{3 is sele,c atendd f -rNomR13–RH1,4; -halo, -OH, -C1-6alkyl, and -C3-6cycl}

2_{0 optionally and independently su oalkyl; wherein each of said -C1-6alkyl is R OR28, and -NR1 bstituted with from 1 to 3 substituents selected from–halo,– NR17R18,e -C ea3-c6ch5}

4 _{and R8 ar y iR}

c_nld16

o_e;

a_{plkeynl,d -eOn-tCly3- s6ecylecclted from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - R6, R7, R9, R10, R11, R12, R13, R14, R15, Ro1a6,lk Ryl1,7, -A Rr4}

1_{8 and -Het4; 25 R35 and R36 are each independ , R19, R20, R21, = R22, R23, R24, R31, R32, R33, R34,}

- _{inSd-Cepeanldkeynl,tl -yC s3-u6cbysctiltouatelkdyl, w -iAthre6n}

f_{r at}

o_nly

m_{d s–e}

1_Hle

t_ec

o_tt6e;d

3 _{w fr}

s_{ho –}

u_em

b_rsetiinH

t_{ue e,}

n_{a -h}

t_ca

s_hlo

s _o,

e_{fle sO}

c_a,

t_{ied -O}

d _-CH

f_r1,

o_{-6 - maClk1- –y6}

h_lalky

a _{islo, ol,p -O-C1-6 1-6 alkyl, –tOioHna,ll -yO a-Cn1d-} R ^{6aldky Rl, -S-C1-6aaclkhy iln,d -Ce3p-6ecnydcelonatllyky sle,l -eHcetet6d, - fArorm6 a–nHd,– -NR37R38}

2^{7 an 28 are e ; 0} _{R R ch independently selected from–H,} ^C -¹ _h ^-6 _a ^a _lo ^lk _, ^y -^l, _O -_H ^C _, ^3-6 _-C ^cy ₁ ^c _-6 ^l _a ^o _l ^a _k ^l _y ^k _l ^y _, ^l - ^a _O ⁿ-^d _C1 --^H _6a ^e _l ^t _k ²

3_{7 and 38 are ea y} ^:

3 _{l, -S-C1- X} ^6alky _e ^l _l ^, _e -_c ^C _te ^3- _d ⁶

1 _{is s} ^cy _fr ^c

,_o ^lo _m ^alk

and_– ^y _C ^l,

-₁O- -₆ ^A

-_a ^r

;_l ⁷ _k w_y ^a _lh-ⁿ _, ^d

er_– ^–

e_O ^H

in-^e _C ^t7

e₁ ^;

a_-6c_ah_lky o_l-f_, s_–a_Sid_-C -₁C_-6

1_a-6lka_ylk_l-y_,l- _-C is_1-6 o_ap_lkti_yo_l-n_Na_Rlly_3-C a₁n-d_6al i_kn_yd_l-e_,pe _-Nn_Rde_3-n_Ctl₁y- ₆alkyl-, -NR₃- -214- s_C ^u ₁ ^b-^st _l ⁱ _k ^tu _y ^{ted with from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6al} s_{6aeleclt,e -dph} ^{kyl, -S-} X _{feronmyl, a–nCd1-6 -aNlRky3l3-R,3–4}

2 _{is ;O-C1-6alkyl-,–S-C1-6}

6^a _{alkyl-, -C1-6alkyl-NR} ^ll _{2-C1-6alkyl-, -NR2-C1-} 5 ^{sulbksytl-it,ut -eNdR w2-i,th a fnrodm -O 1- t;o w 3h seurbesintitu eeancths s oefle scatiedd - fCro1m-6a–lkhyal-lo, is -O oHp,tio -Cn1a-6aylk aynl,d -O in-Cde1-p6aelnkdyle,n -tSly- Ar1, C A1r-6}

4^{,a Alkry5l,, -phenyl and -NR31R32;}

c^{omprisin Agr61, t aond 3 Ar7 are each independently a 5- to 10-membered aromatic cycle optionally} ₁₀ ^{Ar7 being optionall hye atenrdo iatoms selected from O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and} – _{ish oaploti,o -nOaHlly, - aCn1d-6a inlkdyl, -O-} ⁿ _C ^d ₁ ^e _-6 ^p _a ^e _lk ⁿ _y ^d _l ^e _, ⁿ _-S ^tly _-C ^s ₁ ^u _-6 ^b _a ^s _lk ^ti _y ^tu _l, ^te _a ^d _nd ^w _– ^it _N ^h _R ^fr ₁ ^o ₉ ^m _R2 ¹ _0; ^t _w ^o _h ³ _er ^s _e ^u _i ^b _n ^s _e ^ti _a ^tu _c ^e _h ⁿ _o ^ts _{f s} ^s _a ^e _i ^l _d ^ec -^t _C ^e ₁ ^d _-6 ^f _a ^r _l ^o _k ^m _{yl Het1, Het2, Het4, Het5, Heepte6,nd aenndtl Hye stu7b asrteitu eteadch w iinthde frpom 1 to 3 -halo;}

h_{aving from 1 to 3 heteroatoms selected from O,e Nnd aenndtly S; a w 3h- to 10-membered heterocycle Het4, Het5, Het6, and Het7 is optionally and independently seurebisntit euach of said Het1, Het2, 15 substituents selected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-t6eadlky wl,it =hO f}

6^a _{,ro -m}

_{(C= 1O t)o-C13-} s^{ulbksytl, and -NR21R22; wherein each of said -C1-6alkyl is optionally and ind}

^{20 S; 3itu-t teod 1 w0-itmh p d tly Het8 is a e frmombe 1re tdo h 3e -thearoloc;ycle having from 1 to 3 heteroatoms selected from O, N and w sehleerceteind s fraoidm H–ehta8lo is, - oOpHtio,n–aClly1-6 aanlkdyl, in -dCe1p-6eanlkdyelenntley, s -uCb1s-6taitluktyed with from 1 to 3 substituents O-C lkyl, -S-C1-6alkyl, =O, -}

^{(C=O)-C1-6alkyl, -C1- l-C3-6cycloalkyl, -C3-6}

1^{-6a cycloalkyl, - each of said -C 6}

1^{-6alkyl is optionlly d idp dentlya slkuybl-sO-C1-6alkyl and -NR21R22; wherein} ₂₅ ^{wherein when R1–H,hen at le t ht tm of Het8 itsitu attetadc wheitdh t foro Xm21 to 3 -halo;}

Z₁ ^t

A_{1, a Zn2d, Z A3}

2_{, a Zr4e a enadc Zh5 in adreep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and 2 R.1 is se Ale ccotemdp foruonmd– aHs, de–fhinaelod, in -O cHla,im -C 11,-6 wherein}

3_{0 ( wCh=}

b_eS

s_{rte)- itiunR4}

e _e,

n_{a - tscShO}

s_{e o2}

l_ef-R

c _s4

t_ea,

d_{id -C}

f_{r -oCN, -NR9-SO2-Ra4lkyl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - m1-6–ahlkayllo, is -O oRpt , -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; su 3i5o,nally and independently substituted with from 1 to 3 R s} ⁶ _{attached to Z1 or Z5 and is selected fro -NmR–11HR,1–2,h -aOlo-C, -1O-6aHlk,y -lC, a1-n6adlk -ySl-,C -O1-6}

5 _{i Ha,lk -yCl;1-6alkyl, -O-C1-} ^{35 - inOal}

d^-k

e^{Cyl, -S-C1-6alkyl, -NR6R7, -(C=O)-R8, -(C=S)-R8}

p^{3e-6ncdycelnotalylk syul,bs -tAitur5ted an wdith– frHoemt5; 1 t woh 3e sreuibnsti e,}

t^{ua - ecSO2-R8, -CN, -NR6-SO2-R8, -C3-6cycloalkyl, nhts of said -C1-6alkyl is optionally and} O_-C ^{selected from–halo, -OR36, -NR23R24} 1_-6a ^{, -} R_{2 is selectelkdyl f,ro amnd– -HS,-C -h1-6alkyl;}

o_{OpRti2o7n,a alnlyd a -NndR1 in3Rde alo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl is 40 14p;endently substituted with from 1 to 3 substituents selected from–halo,–} -215- R^{3 is o spetiloencatelldy f arnodm in–dHe,p -heanldoe,n -OtlyH s,u -Cbs1-t6itaulkteydl, w anitdh - fCro3m-6cy 1c tlooa 3lk syul;b wshtietureenints ea sechl of said -C1-6alkyl is OR2 ected from–halo,– 5 R 8}

4 ^a

R_{6, R} ^{NndR1 R,8 a}

7^{R an}

1^8r,ed

-^{C e -Na3-cR}

6^ch15

y ^iR

c^nld16

o^e;

a^{plkeynl,d -eOn-tCly3- s6ecyleccloteadl from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -} R₇

3_{,5 R a9n,d R R10}

3_{,6 R ar1e1, e Ra1c2,h R in1d3,e Rpe14n,d Re1n5t,ly R s16e,} ^k

l_{e R} ^yl

c₁ ^,

t₇ - e_, ^A

d _R ^r4

f_1r8 ^a

o_, ⁿ

m _R ^d _1–9 - H_, ^H _R ^et4

, _-2h0 ^; _{,a Rlo2,1 =,O R,22 -,O RH23, R24, R31, R32, R33 R34, -S-C1-6alkyl, -C3-6cycloalkyl, -Ar6 and–Het6; wherein each o , -C1-6alkyl, -O-C1-6alkyl, independently substituted with from 1 to 3 substituents sf said -C1-6alkyl is optionally and} ^{10 S-C N} _{elected from–halo,–OH, -O-C1-} R ^{6alkyl, -} R_{37 and R38, a} ^r _r ^e1- e ^e6a

e^al

a^ck

c^hyl,

h ^{in -} i_n ^dC

d^e3

e^p-6

p^ecy

e^nc

n^dl

d^eo

e^na

n^tllk

t^yy

l_y ^sl,

s^{e - A}

e^lHe _le ^ce

c^tte6,

t_e ^{d -} d ^fr _f ^or6

r_o ^{m an}

m^–dH _–H ^,–

, ^-CR37

2^{7 and R28, a} _-h ^1- _a ^6aR

l_o ^lk38

,^y;

-^l _O ^{, -} _H ^C _, ³ -^-6 _C ^c ₁ ^y-^c _6a ^lo _lk ^a _y ^lk _l, ^y -^l _O ^an _-C ^d ₁ -_-6 ^H _a ^e _lk ^t2 _y ^: _{l, -S-C1- X} ⁶ _s ^alk _s ^y _e ^l _l ^, _e -_c ^C _te ^3- _d ^6cy _fr ^c _o ^lo _m ^alk _– ^y _C ^l, _1- -₆ ^A _a ^r _l ⁷ _ky ^a _l- ⁿ _, ^d–Het7

1 _i ^;

1⁵ _{–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1- X} ⁶

2 _is ^alk _s ^y _e ^l _l-_e ^, _c -_t ^N _e ^R _d ^3- _fr ^a _o ⁿ _m ^d– _– ^O _C-₁ ^; _{-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} A^{r 6}

1^{, c Aa}

o^rlk

m^4,yl-,

p ^{Arirs5 - i,N}

n ^AR

g^r2

6- ^1,,

t ^{a a}

o^nndd

3 ^{A -O}

h^er7-;

t^{e arroeat eoamcsh s inedleecpteendd feronmtly O a, 5 N- to 10-membered aromatic cycle optionally 20 A–hralo,in -OgH o,p -tCio1n-6aalllyky al,n -dO i-nCd1e-6paelknydle,n -Stly-C s1u-6bstituted w ainthd f Sro;m ea 1ch to o 3f s sauibds Atitru1e,n Atrs4, s Aelre5,ct Aerd6}

7 ^{be , fr aonmd} i_{s optionally and independently substi} ^{alkyl, and–NR19R20; wherein each of said -C1-6alkyl} H_{et1, Het2, Het4, Het5, Het6, and Het7 aretu eteadch w iinthde frpoemnd 1e tnotl 3y - aha 3lo-; t}

2_{5 having from 1 to 3 heteroatoms selected from O, N and S; wheroei 1n0 e-macehmbered heterocycle}

H _{suebt4s,tit Hueent5t,s H seetl6e,ct aendd fr Homet7–h isal oop,t -ioOnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-tCitu1-t6ead o}

l_{ky wf}

l_{,it said Het1, Het2, =hO f,ro -m(C= 1O t)o-C13-} 6^{albkyl, and -NR21R22; wherein each of said -C1-6alkyl is optionally and i}

^{30 8 s}

S ^iu

;^{s ast 3itu-t teod 1 w ndp d tly Het 0-itmhe frmombe 1re tdo h 3e -thearoloc;ycle having from 1 to 3 heteroatoms selected from O, N and w sehleerceteind s fraoidm H–ehta8lo is, - oOpHtio,n–aClly1-6 aanlkdyl, in -dCe1p-6eanlkdyelntly substituted with from 1 to 3 substituents} O_{-C1-6alkyl, -S-C1-6alkyl, =O, -(C=} ^{ene, -C1-6alkyl-C3-6cycloalkyl, -C3-6cycloalkyl, -} _{35 each of said -C1-6alkyl is opt}

_{O)-C1-6alkyl, -C1-6alkyl-O-C1-6alkyl and -NR21R22a;lo w;herein Z1, wherein when R1 is–H, thenio ant lllytd id hpt daetonmtly o sfubstituted with from 1 to 3 -h a Zn2d, Z A3}

2_{, a Zr4e a enadc Zh5 in adre Het8 is attached to X2 A1 ep eeancdhe inntdlyep seenledcetendtly fr soemle Ccte adnd fro Nm. C and N; and 3. A compound as defined in claim 1, wherein} -216- R^{1 is( selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - wCh=eSre)-inR4 e,a -cShO o2f-R4, -CN, -NR9-SO2-R4, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; 5 substituents selec steadid fr -oCm1-6–ahlkyl is optionally and independently substituted with from 1 to 3 R5 is -N aRtta6Rch7,e -d(C to=O Z1)- oRr8 Z, -5(C an=dS i)s-R sa}

8^el

,^loe,

-^{ScOt -eO}

2^dR

-^{R f3r5}

8^o,

,^{m -N}

-^C–R

N^H1

,^,1R

-^N–1h2

R^{a,l - 6-oO-C1-6alkyl, and -S-C1-6alkyl;}

S^{,O -O2H, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, Ar5 and–Het5; wherein each of said -C1-6alkyl is optiona-Rlly8, a -nC3-6cycloalkyl, -O-C3-6cycloalkyl, - from 1 to 3 substituents selected from–halo, -OR36, -NR23R24,d -O in-dCe1p-6eanlkdently substituted with R selected from–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein eayclh, a onfd s -S-C1-6}

2 ^{is alkyl; 10 o} _O ^p _R ^ti ₂ ^o ₇ ⁿ _, ^a _a ^l _n ^ly _d ^a _-N ^nd _R1 ⁱⁿ _3R ^de ₁₄ ^p _; ^{endently substituted with from 1 to 3 substituents selectedai fdro -mC1–-6haalkloyl, i–s} R_{3 is o spetiloencatelldy f arnodm in–dHe,p -heanldoe,n -OtlyH s,u -Cbs1-t6itaulkteydl, w anitdh - fCro3m-6cy 1c tlooa 3lk syul;b wshtietureenints ea sechle octfe sdai fdro -C1-6alkyl is 15 OR28, and -NR15R1 m–halo,– R NndR1 R7R18,e -O ea-Cch3-6 incyd6}

4 _{a 8 ar ce;}

l_{poeanlkdently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - R, R7, R9, R10, R yl, -C3-6cycloalkyl, -Ar4 and -Het4}

6 _;

R _{11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33, R34 20 -S3-5C a1n-6dal Rky3l6, a -Cre3- e6caycchlo inadlkeypl,e -nAdre6ntly selecte;d w from–H, -halo, =O, -OH, -C1-6alkyl, -O-C1-6alkyl, independently substituted with fr aonmd– 1H teot63 shuebrsetiintue enatcsh s oefle scatiedd -C fr1o-6malk–yhla islo, op–tOioHna,ll -yO a-Cn1d-} R ⁶

2^{7 aanldky Rl,28 -} 8^,S

, ^a-C

a^r _r ^e1- e ^e6a

e^al

a^ck

c^hyl,

h ^{in -} i_n ^dC

d^{e3 yc}

e^p-6

p^ec

eⁿ _n ^dl

d^eo

e^na

n^tllk

t^yy

l_y ^sl,

s^{e -} e^lHe _le ^{ce A}

c^tte6,

t_e ^{d -} d ^fr _f ^or6

r_o ^{m and–NR37R38;}

R_{7 and R3 m} ^–H _–H ^{, -} _, ^C _-h ^1- _a ^6a _lo ^lk _, ^y -^l _O ^{, -} _H ^C _, ³ -^-6 _C ^c ₁ ^y-^c _6a ^lo _lk ^a _y ^lk _l, ^y -^l _O ^an _-C ^d ₁ -_-6 ^H _a ^e _lk ^t2

3 _y ^: _{l, -S-C1- 25 X} ⁶

1 _is ^alk _s ^y _e ^l _l ^, _e -_c ^C _te ^3- _d ^6cy _fr ^c _o ^lo _m ^alk _– ^y _C ^l, _1- -₆ ^A _a ^r _l ⁷ _ky ^a _l- ⁿ _, ^d _– ^– _O ^H-^e _C ^t7

1^; _{-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbksytl-it,ut -eNdR w3-i,th a fnrodm -O 1- t;o w 3h seurbesintitu eeancths s oefle scateidd f -rCo1m-6a–lkhyal-lo i,s -O oHpt,io -Cna1-l6laylk aynl,d -O in-Cde1-p6aelnkdyle,n -tSly- 30} _{X C1-6alkyl, -phenyl, and -NR33R34}

2 _{is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} 6 ^{saulbksytl-it,ut -eNdR w2-i,th a fnrodm -O 1- t;o w 3h seurbesintitu eeancths s oefle scatiedd - fCro1m-6a–lkhyal-lo, is -O oHp,tio -Cn1a-l6laylk aynl,d -O in-Cde1-p6aelndently C1-6alky}

c^ompris5l

i^,,

n ^{A -p}

g^rh61,e

t ^an

o^{ny kyl, -S- Ar Ar dl a}

3 ^An

h^{erd7 - te aN}

r^rR

o^e3

a^{t e1R}

o^amc32

1^{, 4, Ar sh;}

s ^{inedleecpteendd feronmtly O a, 5 N- t aond 10 S-m; eeamcbhe orefd sa aidrom Ara1,tic Ar c4y,c Aler5, optionally 35 A} _–h ^{r7 being optionally and independently substituted with from 1 to 3 substituents select Aerd6, fr aonmd} i_{s oaploti,o -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and–NR19R20; wherein each of said -C1-6alkyl Het1, Het2,n Haellty4, a Hndet i5n,d Heepte6,nd aenndtl Hye stu7b asrteitu eteadch w iinthd from 1 to 3 -halo;}

h_{aving from 1 to 3 heteroatoms selected from Oep,e Nnd aenndtly S; a w 3h-e troei 1n0 e-macembered heterocycle 40 Het4, Het5, Het6, and Het7 is optionally and independently substitutedh o wfit shaid fro Hmet11, H toet23,} -217- substituents selected from–halo, -OH,–C_1-6alkyl, -O-C_1-6alkyl, -S-C_1-6alkyl, =O, -

(C=O)-C_1- 6 ^{saulbksytl,itu atendd w -iNthR fr2o1Rm221; to wh 3e -rhein each of said -C1-6alkyl is optionally and indp d tly 5 Het8 O is, N a a bnivda Sle;nt 3- to 10-membearleod; heterocycle having from 1 to 3 heteroatoms selected from w whheerreeiinn a wth leenas Rt1 o inse– oHf, s tahiedn h aette leroaastto omnes i hse atettraocahtoed to X1 or X2;}

w^{herein said Het8 is optionally and indepe m of Het8 is attached to X2; and} s_{elected from–halo, -O} ^{ndently substituted with from 1 to 3 substituents} _{10 O ea-Cch1-6 oaflk syali,d - -SC-1C1-6}

-_{6alkaylkly isl,H}

o _=,

p_O–C

t_{,1 --}

_{(6Cal=kOyl),-C -C1-6}

1_{-6aalklkyyl,le -nCe1,-6 -aClk1-y6la-Olk-yCl-1C3-6}

-_{6alckyycllo aanldky -l,N -RC3-6}

2_{1Rc2y2;clo wahlkeyrel,in - Z1, Z2, Z3, Z4 and Z5 a ionlly d idp dently substituted with from 1 to 3 -halo;}

A_{1 and A2 are each indreep eeancdhe inntdlyep seledctedtly froml Ct adnd fro Nm. C and N; and 15 4 p.redrug, A sa clot,m hpydoruantde, o Nf-o Fxoidrmeu folarm Ia, o orr so alva stteer tehoeisreoomf,er, tautomer, racemic, metabolite, pro- or}

W^herei

^{I 20 R1 is(C snelected from–H,–hal, -OH, -C- lkyl, -O}

w^{h=S)-R4, -SO2-R4, -CN, -NR9-SO2-R4, -C3-6cy-Cclo-alklkyyl,l, - -OS--CC- 3-6acylkcylol,a -lNkyRl,9R -A10r,1 -( aCn=dO)–-HRe4,t1 -; subesrteitiune enatsch se olefc steadid fr -oCm1-6–ahlkayllo, is -O oRpt3i5o,n -aNlRly11 aRn1d2, i -nOdependently substituted with from 1 to 3 R5 is attached toO Z1 or Z5 and is selected f -C1-6alkyl, and -S-C1-6alkyl; l,} _{25 A} ^-N

f_rr5 ^{R rom–H,–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6} a^6R _nd ^7, _– ^{-( alky} H^C _e ⁼ _t5; ⁾ _w ^-R _h ⁸ _e ^, _r -_e ⁽ _i ^C _n ⁼ _e ^S _a ⁾ _c-_h ^R8 _o ^, _f - _s ^S _a ^O _id ^2-R _-C ⁸

1^,- -₆ ^C _al ^N _ky ^, _l ^-N _is ^R _o ⁶ _p ^-S _tio ^{O2-R8, -C3-6cycloalkyl, -O-C3-6cycloalkyl, -} s _{soem 1 to 3 substituents sel nally and independently substituted w;ith R2 i ected from–halo, -OR36, -NR23R24, -O-C1-6alkyl, and -S-C1-6alkyl optiloencatelldy f arnodm in–dHe,p -heanldoe,n -OtlyH s,u -Cbs1-t6itaulkteydl, w and -C3-6cycloalkyl; wherein each of said -C1-6alkyl is 30 isO}

o _sR

p_{e2 ith from 1 to 3 substituents selected from–halo,– R tiloe7, 8nc a ,atendd alnly f - d arN -NnodmR13 R1 in–R 5RdH1}

e_,4

3 _{; 16p -h}

;_{eanldoe,n -OtlyH s,u -Cbs1-t6itaulkteydl, w anitdh - fCro3m-6cy 1c tlooa 3lk syul;b wshtietureenints ea sechle octfe sdai fdro -mC1–-6haalkloyl, i–s OR2} -218- R^{4 aNndR R8 are each independently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6}

1^{7R18, -C3-6cycloalkyl, -O-C3-6 alkyl, - R6, R7, R9, R10, R11, cycloalkyl, -Ar4 and -Het4;} 5 _{R nd R} ^{R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33}

3_{5 a 36 are eac} ^R34, - _{inSd-Cep1-e6anldkeynl,tl -yC s3- h independently selected from–H, -halo, =O, -OH, -C1-6alkyl, -O-C1-6alkyl, u6cbysctiltouatelkdyl, w -iAthr6 fr aonmd– 1H teot6; 3 w shuebrsetiintue enatcsh s oefle scatiedd -C fr1o-6malk–yhla islo, op–tOioHna,ll -yO a-Cn1d} a^l - R ^{a 6ndky Rl,28 -,S a-Cre1- e6aalckhyl, in -dCe3p-6ecyncdleonatllkyy sl,e -lHecette6,d -A fror6m an–dH–NR37R38}

2^{7 ;}

R_{37 and R38, are each independently selected from–H} ^{, -} _, ^C _-h ^{1-6alkyl, -C3-6cycloalkyl and -Het2:}

1⁰ _{alo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- X} ⁶

1 _is ^alk _s ^y _e ^l _l ^, _e -_c ^C _te ^3- _d ^6cy _fr ^c _o ^lo _m ^alk _– ^y _C ^l, _1- -₆ ^A _a ^r _l ⁷ _ky ^a _l- ⁿ _, ^d _– ^– _O ^H-^e _C ^t7

1^; _{-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} 6 ^{saulbkyl-, -NR3-, and -O-; wherein each of said -C1-6alkyl- is optionally and independently} C₁ ^{stituted with from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-} _{15 X -6alkyl, -phenyl, and -NR33R34}

2 _{is s} ^y _e ^l _l-_e ^, _ct -_e ^N _d ^R2 _f-_r ^, _om ^and _–C -₁ ^O _-6-_a ^; _lk ^w _yl ^h _-, ^er _– ^e _O ⁱⁿ _-C ^e ₁ ^a _-6 ^c _a ^h _lky ^o _l ^f _-, ^s _– ^a _S ^id _-C -₁ ^C _-6

1_a ^-6 _lk ^a _y ^l _{l-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2} 6^alk _-C1- s^{ubstituted with from 1 to 3 substituents selected from–khyal- is optionally and independently C1-6alk lo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S- Ar1, Ar4, Ary5l,, A -prh6,e annydl a And -NR31R32;}

2^{0 c Aor7m bperiisnigng op 1tio tona 3ll hyer7}

a^{te a}

n^rr

d^oe

i^{a each independently a 5- to 10-membered aromatic cycle optionally ntdoempse selected from O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and} –_{halo, -OH, -C1-6alkyl, -O-C1-6} ^{ndently substituted with from 1 to 3 substituents selected from} i_{s optionally and independenalkyl, -S-C1-6alkyl, and–NR19R20; wherein each of said -C1-6alkyl 25 Het1, Het2, Het4, Het5, Het6, andtl Hye stu7b asrteitu eteadch w iinthde frpoemnd 1e tnot 3 -halo;}

h _{Haevt4in,g H ferot5m, H 1e tto6, 3 a hnedte Hroeat7tom iss o spetlioenctaeldly fr aonmd O in,d Nep aenndly}

d_{e Sn; a}

t_{l w 3}

y_{h- se t}

u_{roebi 1}

s_n0

t_{it e-membered heterocycle uatecdh of said Het1, Het2, substituents selected from–halo, -OH,–C1-6alkyl, -O-C1-6alkyl, -S-C1-6alky wl,it =hO f,ro -m}

_{(C= 1O t)o-C13-} 6^{alkyl, and -NR21R22; wherein each of said -C1-6alkyl is optionally and indp d tly 30 Het8 s}

S ^{iusb ast 3itu-t teod 1 w0-itmhe frmombe 1re tdo h 3e -thearoloc;ycle having from 1 to 3 heteroatoms selected from O, N and w;}

s_O ^eher

-^l _C ^{eceteind s fraoid}

,^{m H}

-_S ^–e

-_C ^{hta8lo is, - oOpHtio,n–aClly1-6 aanlkdyl, in -dCe1p-6eanlkdyelenntley, s -uCb1s-6taitluktyel-dC w3-6ith from 1 to 3 substituents} _{35 1-6alkyl 1-6alkyl, =O, -}

_{(C=O)-C1-6alkyl, -C1-6al} ^c _k ^{ycloalkyl, -C3-6cycloalkyl, -} e _{wahcehre oinf s wahiden -C R1-6}

1_{a islk–yHl i,s optionlly d idp dently skuybl-sOtit-uCt1e-6da wliythl a frnodm - 1N tRo231R -2h2a;lo w;herein Z Z4 and Z5 are each th iennde apte lndetntly s heletctedat foromm o Cf H aentd8 i Ns. attached to X2}

1_{, Z2, Z3,}

5_{. A compound as defined in claim 4, wherein} -219- R^{1 is(C s=eSle)-cRte4,d - fSroOm2-R–H4,, -–ChNa,lo, -N -OR9H-S,O -C1-6}

2^{-Ra4,lky -Cl,3 --6O-C1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - w cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; 5 suhbesrteitiune each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 R5 is -N aRtta6Rch7,e -dnt}

(^{C tso s}

=^{O Ze1le}

)^{- oc}

R^rte

8 ^Zd

, ^{-5( a frnodm is–h saelloe,ct -eOdR f3r5o,m -N–RH1,1R–1h2a,l -oO,- -CO1H-6,a -lkCy1l-,6a alnkdyl -,S -O-C-C1-6}

1^{a-6laklykly;l, -S-C1-6alkyl, Ar5 and–Het5; whereiCn=S)-R8, -SO2-R8, -CN, -NR6-SO2-R8, -C3-6cycloalkyl, -O-C3-6cycloalkyl, - from 1 to 3 substituents e saeclh of said -C1-6alkyl is optionally and independently substituted with R2 is selected from–H, -halo, -eOcted from–halo, -OR36, -NR23R24, -O-C1-6alkyl, and -S-C1-6alkyl; 10 i} _– ^s

_O ^o _R ^p ₂ ^t ₇ ^io _, ⁿ _a ^{ally and independentHly, s -Cub1-s6atiltkuytel,d an wdith -C fr3o-6mcyc 1lo toalk 3y sl,u;b wshtietureeinnts ea scehle octfe sdai fdro -mC1–-6haalkloy,l} R_{3 iptil tn}

l_{lydd f -NR1}

d _id–3RH14;

p _{-hdaelon,tl -yO sHu,bs -Cti1-6alkyl, -C3-6cycloalkyl; wherein each of said -C1-6alkyl is 15 OR28, and -NR15R16 tuted with from 1 to 3 substituents selected from–halo,– R4 a NndR R8 are each inde;pendently selected from–halo,–OH, -C1-6alkyl, -O-C1-6}

1_{7R18, -C3-6cyclo alkyl, -S-C1-6alkyl, - R6, R7, R9, R10, R11, R12a,lk Ry1l3,, -O R1-C4,3 R-6c15y,c Rlo1a6,lk Ryl1,7, -A Rr4}

1_{8 a,n Rd19 -,Het4;}

R _{36 are each independently selected from–H R,2 -0h,a Rlo2,1, R22, R23, R24, R31}

3_{5 and R , R32, R33, R34, 0 -S-C1-6alkyl, -C3-6cycloalkyl, -Ar6 and–Het6; wherein each of =O, -OH, -C1-6alkyl, -O-C1-6alkyl, 2 i} ⁶ _n ^a _d ^lk _e ^y _p ^l, _e -_n ^S _d-_e ^C _n ¹ _t-_l ⁶ _y ^alk _s ^y _u ^l _b ^, _s -_{tituted with from 1 to 3 substituents sele scatiedd -C fr1o-6malk–yhla islo, op–tOioHna,ll -yO a-Cn1d-} R ^{C3-6cycloalkyl, -Het6, -Ar6 and–NR37}

2^{7 and R38;}

R ^{R28, are} _e ^e _e ^a _a ^c _c ^h _h ⁱⁿ _in ^d _d ^e _e ^p _p ^e _e ⁿ _n ^d _d ^e _e ⁿ _n ^tl _t ^y _ly ^s _s ^e _e ^le _le ^c _c ^te _te ^d _d ^fr _f ^o _ro ^m _m ^–H _–H ^{, -} _, ^C _-h ^1- _a ⁶

3_{7 and R38, ar} ^a _lo ^lk _, ^y -^l _O ^{, -} _H ^C _, ³ -^-6 _C ^c ₁ ^y-^c _6a ^lo _lk ^a _y ^lk _l, ^y -^l _O ^an _-C ^d ₁ -_-6 ^H _a ^e _lk ^t2 _y ^: _{l, -S-C1- 25 X} ⁶ _s ^alk _s ^y _e ^l _l ^, _e -_c ^C _te ^3- _d ^6cy _fr ^c _o ^lo _m ^alk _– ^y _C ^{l, -} ₆ ^A _a ^r _l ⁷ _ky ^a _l- ⁿ _, ^d _– ^– _O ^H-^e _C ^t7

1 _{i 1- 1} ^; _{-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1- X} ⁶

2 _is ^alk _s ^y _e ^l _l-_e ^, _c -_t ^N _e ^R _d ^3- _fr ^a _o ⁿ _m ^d– _– ^O _C-₁ ^; _{-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-} ^{30 Ar 6alkyl-, -NR2}

1^{, Ar4, Ar5, -, and -O-;}

c ^{is matic cycle optionally Aor7m bperinign Agr6}

o^{p 1,}

t^{io t aond}

n^{a 3 A}

l^{l hyer7 are each independen}

a^{tenr tly a 5- to 10-membered aro}

d^{o iantdoempse selected from O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and –halo, -OH, -C1-6alkyl, -O-C1-6anlkdyently substituted with from 1 to 3 substituents selected from} o_{ptionally and independently subst} ^l _i ^, _t ^{-S-C1-6alkyl,–NR19R20; wherein each of said -C1-6alkyl is} _{35 Het1 h, Het2, Het4, Het5, Het6, and Het7 aurete eda wcihth in frdoempe 1n tdoe 3nt -lyha alo 3;- to 10-memb}

H_{aevt4in,g H ferot5m}

t_{,s H 1}

s_{e t}

e_to

l_{6e, 3}

c_{t a h}

e_ne

d_dte

f_{r Hro}

o_meat7tom

–_{h iss}

a_{l o s}

o_pe

,_tl

-_ioe

O_nct

H_aed

,_{lly fr}

–_{C ao}

1_nm

-_{6d O}

a_{lk in,}

y_{d Ne and S; wherein each ofer seadid h Heetet1ro,c Hyectl2e, substituen l, -pOe-nCd1e-6natllkyyl s,u -bSs-tCitu1-t6eadlky wl,it =hO f,ro -m(C= 1 to} 6^a _{O)-C13- su} ^l _b ^k _s ^y _t ^l, _itu ^a _te ⁿ _d ^d _w -_i ^N _th ^R _fr ² _o ^1R _m ²² ₁ ^; _to ^wh ₃ ^e -^r _h ^e _a ⁱⁿ _lo; ^{each of said -C1-6alkyl is optionally and ind}

^{p d tly} -220- H^{et8 S is}

w^{; a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and sehleerceteind said Het8 is optionally and independently substituted with from 1 to 3 substituents 5 O-C1-6alky frlo,m -S–-Cha1-l6oa,lk -yOl,H =,O–C,1 --}

^{(6Cal=kOyl),-C -C1-6}

1^{-6aalklkyyl,le -nCe1,-6 -aClk1-y6la-Olk-yCl-1C3-6}

-^{6alckyycllo aanldky -l,N -RC3-6}

2^{1Rc2y2;clo wahlkeyrel,in - e wahcehre oinf s wahiden -C R1-6}

1^{a ilkyl is optionlly d idp dently substituted with from 1 to 3 -halo;}

Z ^{s–H, then at l t ht atom of Het8 is attached to X2}

1^{, Z2, Z3, Z4 and Z5 are each independently selected from C and N.}

1^{0 6 R.1 is(C s=e A}

S^{le c}

)^-co

R^tem

4^,dp

- ^fo

S^ruon

O^md

2^{-R– aHs}

4^{,, de}

-^–f

C^hin

N^ae

,^{lod, in}

-^{N -O c}

R^9Hla

-^S,im

O ^{-C 41-6 w}

2^-Rah

4^,lkeyr

-^Cle,in

3 ^{--6Ocy-Cc1-6alkyl, -S-C1-6alkyl, -NR9R10, -(C=O)-R4, - wherein each of said -C1-6alkyl is optionally andl ionadlkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1;} s_{ubstituents selected from–halo, -OR35, -NR11R12, -O-} ^e _C ^p ₁ ^e _-6 ^{ndently substituted with from 1 to 3} _{15 R5 is -N aRtta6Rch7,e -d(C to=O Z1)- oRr8 Z, -5(C an=dS i)s-R s8e,le -ScOte2d-R fr8o,m -C–NH,, -N–hRa6l-oS,O -O2-HR,a}

8_{, -lkCy}

-_C1l-,6

3_{-a a}

6_{clnkd -S}

y_{yl, -O-C-C1-6}

1_{a-6laklykly;l, -S-C1-6alkyl, Ar5 and–Het5; wherein each of said -C1-6alkyl is optionally and incloalkyl, -O-C3-6cycloalkyl, - from 1 to 3 substituents selected from–halo, -OR36, -NR23R24, -O-dCe1p-endently substituted with 20 R -halo, -OH, -C 6}

2 _{is selected from–H, 1-6alkyl, and -C3-6cycloalkyl; whe alkyl, and -Sd-C1-6alkyl; optionally and independently substituted with from 1 to 3 substitureenints ea sechle octfe sdai fro -mC1–-6haalkloyl, i–s R is O}

o _sR

p_e2

t_iloe7,

n_{c a}

a_ten

l_ldd

y _{f - arN}

n_odmR13

i_n–R

d_H1

e_,4

3 _;

p _{-heanldoe,n -OtlyH s,u -Cbs1-t6itaulkteydl, w anitdh -C3-6cycloalkyl; wherein each of said -C1-6alkyl is 25 OR2 R1 from 1 to 3 substituents selected from–halo,– R 8}

i_{n6d,e Rpe7,nd R,}

e_{9 a}

n_,n

t _Rd

l_{y1 -0N,R}

s_{e R15}

l_{e11c,te R6;}

d_{12, fr Rom13,– RH14,, R -h1a5,lo R,16 =,O R,19 -,O RH2,0, - RC21}

1_{-6,a Rlk2y2l,, R -3O1,-C R32}

1_{-6a,l Rky3l3, a -nSd-C R34}

1_{-6al akryel, e -aCc3h-} 6 _s ^c _u ^y _b ^c _s ^lo _tit ^a _u ^lk _te ^y _d ^l, _w ^-A _ith ^r6 _fr ^a _o ⁿ _m ^d ₁ ^– _t ^H _o ^e ₃ ^t6; _su ^w _b ^h _s ^e _ti ^r _tu ^e _e ⁱⁿ _nts ^ea _s ^c _e ^h _lec ^o _t ^f _ed ^sa _fr ^id _om ^-C _– ¹ _h ^-6 _a ^a _lo ^lk _, ^y _– ^l _O ^is _H, ^o -^p _O ^ti-^o _C ⁿ ₁ ^a _-6 ^l _a ^ly _lky ^a _l ⁿ _, ^d _-S- ⁱⁿ _C ^d ₁ ^e _-6 ^p _a ^e _lk ⁿ _y ^d _l, ^e -ⁿ _C ^{tl ycloa} ₃ ^y- ^{30 6 Rc}

R ^{dlk Ry2l,8 -} 8^{, -H}

, ^a _a ^re

r^et6

e ^e,

e^{a -A an}

a^c _c ^hr6

h ⁱⁿ _in ^dd

d^e _e ^p–

p^eN

e^nR

n^d _d ^e37

2^{7 an} _e ^nR

n^tl3

t^y8;

l_y ^s _s ^e _e ^le _le ^c _c ^te _te ^d _d ^fr _f ^o _ro ^m _m ^–H _–H ^{, -} _, ^C _-h ¹ _a ⁶

3_{7 and R3} ^a _lo ^lk _, ^y -^l _O ^{, -} _H ^C _, ³ -^-6 _C ^c ₁ ^y-^c _6a ^lo _lk ^a _y ^lk _l, ^y -^l _O ^an _-C ^d ₁ -_-6 ^H _a ^e _lk ^t2 _y ^: _{l, -S-C1- X i} ⁶ _s ^alk _s ^y _e ^l _l ^, _e -_c ^C _te ^3- _d ^6cy _fr ^c _o ^lo _m ^alk _– ^y _C ^l, _1- -₆ ^A _a ^r _l ⁷ _ky ^a _l- ⁿ _, ^d _– ^– _O ^H-^e _C ^t7

1 ₁ ^; _{-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-} ^{35 6 sa}

C^{ul 6l}

1^bk

-₆ ^sy

a^tl- lⁱ _k ^t,u _y ^{t -} l_, ^eN

-^dR

p_h ^w3- e^{i,th a fnrodm -O 1- t;o w 3h seurbesintitu eeancths s oefle scateidd f -rCo1m-6a–lkhyal-lo i,s -O oHpt,io -Cna1-laylk aynl,d -O in-Cde1-p6aelnkdyle,n -tSly-} X _lected ² _f-_{ronmyl, a–nCd1-6 -aNlRky3l3}

2 _{is se -R,3–4O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR2-C1-} 6^a

0 _sCu ^l _b ^k

6_s ^y

a_t ^l- l_ikt ^, _ut - y_l,e ^N

-_d ^R

p_{h wei} ^, _tnh ^a

y _f ⁿ

l_{r ao} ^d

n_m ^-O

d ₁- -_{N t} ^;

R_o ^w

3₃ ^h

1_{R s} ^e

3_u ^r

2_b ^e

;_s ⁱⁿ _titu ^e _e ^a _n ^c _t ^h _{s s} ^o _e ^f _le ^s _c ^a _t ⁱ _e ^d _d - _f ^C _ro ¹ _m ^-6a _– ^lk _h ^y _a ^l- _lo, ^is _-O ^o _H ^p _, ^tio _-C ⁿ ₁ ^a-^l ₆ ^l _a ^y _lk ^a _y ⁿ _l, ^d _-O ⁱⁿ _-C ^de _1- ^p ₆ ^endently _{4 1- alkyl, -S-} -221- A^{r1, c Aorm4,p Arirs5i,n Agr61, t aond 3 A her7te arroeat eoamcsh s inedleecpteendd feronmtly O a, 5 N- t aon 1d0 S-m; eeamcbhe orefd sa airdomatic cycle optionally Ar7 being optionally and independently substituted with fr Ar1, Ar4, Ar5, Ar6, and –halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6 om 1 to 3 substituents selected from} 5 _{Het1 i,s H oeptt2io,n Haellty4, a Hndet i5n,d Heepte6,nd aenn} ^{alkyl, and–NR19R20; wherein each of said -C1-6alkyl} d_{tl Hye stu7b asrteitu eteadc with from 1 to 3 -halo;}

h_{aving from 1 to 3 heteroatoms selec h independently a 3- to 10-membered heterocycle Het et ted from O, N and S; wherein each of said Het1}

4_{, Het5, H 6, and Het7 is optio , Het2,} ¹⁰ _{substituents selected from–halo, -OnHa,lly–C a1n-6dalk inydl,e -pOe-nCd1e-6natllkyyl s,u -bSs-tCitu1-t6eadlky wl,it =hO f,ro -m}

_{(C= 1O t} 6^a _)o-C13- s^{ulbksytl,itu atendd w -NR21R22; wherein each of said -C1-6alkyl is optionally and indp d tly Het8 S is; a 3- to 10-itmhe frmombe 1re tdo h 3e -thearoloc;ycle having from 1 to 3 heteroatoms selected from O, N and 15 w wh}

w^heer

e^re

r^{eiinn a wth leenas Rt1 o inse– oHf, s tahiedn h aette leroaastto omnes i hse atettraocahtoemd t oof X H1e ot8r i Xs2 a;ttached to X2; a seh}

-^{lCeceteind s fraoidm H–ehta8lo is, - oOpHtio,n–aClly1-6 aanlkdyl, in -dCe1p-6eanlkdyelenntley, s -uCb1s-6taitluktyel-dC w3-6ith from 1 to 3nd substituents O 6alkyl, -S-C1-6alkyl, =O, -}

^{(C=O)-C1-6a cycloalkyl, -C3-6}

1^{- cycloalkyl, - each of said -C1-6alkyl is opt lkyl, -C1-6alkyl-O-C1-6alkyl and -NR21R22; wherein 20 Z1, Z2, Z3, Z4 and Z5 are each indioenpllyd dtly idlptdde fnrotlmy s Cub asntidtu Nte.d with from 1 to 3 -halo; 7. A} _o ^c _r ^o _p ^m _re ^p _d ^o _r ^u _u ⁿ _g ^d _{, s} ^o _a ^f _l ^F _t, ^o _h ^r _y ^m _d ^u _ra ^la _te ^Ia _{, N} ^o-^r _o ^F _x ^o _id ^r _e ^m _f ^u _o ^la _rm ^I _, ^o _o ^r _r ^a _so ^{stereoisomer, tautomer, racemic, metabolite, pro-} 6_{, wherein each of said Z1, Z2, Z3, Z4 a lvate thereof as defined in anyone of claims 1 to 25 provisions as defined in claims 1 to 6 appnlyd. Z5 is C; and wherein the further definitions and 8 A.}

R_{1 A}

1 _{a isn c}

s_dom

e _{Ale2po aurend ea acsh d ienfdineepden inde onntely o sfe clleacimtesd 1 fro tom 3 C w ahnedre Nin;}

3_{0 R R5}

2 _{i iss s seellecteedd f fr}

e_ct

c_{t roomm––HH, a -nhdal–oh aanlod; -C1-6alkyl;}

R_{3 is selecteedd f frrom–H and -C1-6}

1_{alkyl; X X1}

2 _{is sel oomm l- 35 Het is8 i s ec}

s_{electteedd f frrom––}

-_OH

C_{-1C a1n-6d}

-_{6alka - yllkC}

-_y,–-6,a

O _-l

-_Nky

C_Rl;3

1_{-6-aClk1-y6la-,lk -yNl-R,2 --NCR3}

1_{-6-a,l -kOyl--;, -NR2-, -O- sub asti 3tu-e tnots 10 s-emleecmtebder freodm he–thearlooc,y -cOleH;, w–hCe1r-e6}

6_{ainlk syal,id -C H1-e6at8lk iysle onpeti,o -n;}

C_{a3ll-y6c syuclbosatliktuytle,d -C w1-i6thalk 1yl t-oC33-} Z ⁶

1^{, Z2c,y Zcl3o,a Zl4ky aln,d -}

^{(C Z=O)-C1-6ahlk Cyl, and -(C=O)-C3-cycloalkyl ; and} _{40 9. A compound as defined in claim 8 wherein} -222- A ^R1

1 ^{a isn sde Ale2c atered e fraocmh– inHde apnedn–dheanltoly selected from C and N;}

R

5 ^R5

2 ^{i iss s seelleecctteedd f frroomm––HH, -halo and; -C1-6alkyl;}

R^{3 is s and -C1-6alkyl}

1 _{is sel} ^l _e ^e _c ^c _t ^{te ;}

X ^e

X_{2 is selecteed} ^dr

d _f ^f

f_rro ^o

o_m ^m

m_– ^–

–_O ^H

O_--C ^a

C₁ ⁿ _-6 ^d

1_-6a - a_l ^C

l_kky ¹

y_l- l-⁶

-_, ^a

, _- ^l _N ^ky _R ^l; _{3-C1-6alkyl-, -NR3-, -O-;}

H_{et -NR2-C1-6alkyl-, -NR2}

8 _{is a 3- to 10 -, -O-;} ¹⁰ _{substituents s-emleecmtebdere frdom het–ehroacloy,cle -O;H w,he–rCei1n-6a slakiydl, H -eCt8}

1_{-6 iaslk oypletionnea,ll -yC s3-u6cbysctiltouatelkdyl w,it ahnd 1 t -oC13-} Z ⁶

1^{, Z2a,lk Zy3l,C Z3-6}

4^{c ayncdlo Za5lk ayrle; a enadch C.}

1^{0. A compound as defined in claim 8 or 9 wherein A1 is N and A2 is C.}

1_{5 11. A sa clto,m hypdoruanted, o Nf- Foxoirdmeu floarm Ia, o orr a so slvtearteeo tihseormeoefr,, tautomer, racemic, metabolite, pro- or predrug,}

W^he

^{I 20 R R1 irein R5}

2 ^is

i^{s se s a settl}

l^ae

e^cc

c^hte

t^eed

d^{d f}

f ^tr

r^oom

o ^{Z1– aHnd an isd s–ehleclte;d from–H and -C1-6alkyl;}

R ^{m–H and -C1-6}

X^{3 alkyl;} X¹

2 ^{i iss s seelleected from–H and -C1-6alkyl;} H_{et is8 sele} ^c _c ^t _t ^e _e ^d _d ^f _f ^r _r ^o _o ^m _m ^– _– ^O _O--^C _C ^1-6

1_-6 ^a _a ^l _l ^k _k ^y _y ^l _l--^{, -NR3-C1-6alkyl-, -NR3-, -O-;}

2_{5 w isith a 13- to to 31 s0u-mbsetmitubeenrtesd s Nel-,}

e_{c - coN}

t_nR

e_{tda2i- fnC}

r_{oin1- mg6a hlk}

–_ey

h_{tael- lr,}

o_{o - ,cN}

-_yR

O_{cl2e-,; - wOh-e;rein said Het8 is optionally substituted , ZO-C1-6alkyl, -S-C1-6alkyl, =O, -(C= H1-6,–C1-6alkyl, -C1-6alkylene, -C3-6cycloalkyl, - Z1 2, Z3, Z4 and Z5 are each C. O)-C1-6alkyl, -C alkyl-O-C1-6alkyl and -NR21R22}

_{; and 30} -223- 12. A compound selected from the list comprising:

C

_{p d N1 E pl N1 Cp d N2 E pl N2 C}

_{p d N3 E pl N3 Cp d N4 E pl N4 C}

_{p d N5 E pl N5 Cp d N6 E pl N6 C}

_{p d N7 E pl N7 Cp d N8 E pl N8} -224- _C

_{p d N9 E pl N9 Cp d N10 E pl N10 Cp d N11 E pl N11 Cp d N12 E pl N12 C}

_{p d N13 E pl N13 Cp d N14 E pl N14}

C_o

_{p d N15 E pl N15 Cp d N16 E pl N16} -225- _C

_{p d N17, E pl N17 Cp d N18, E pl N18 C}

_{p d N19 E pl N19 Cp d N20 E pl N20 C}

_{p d N21, E pl N21 Cp d N22, E pl N22 C}

_{p d N23 E pl N23 Cp d N24 E pl N24} -226- _Co

_{p d N25 E pl N25 Cp d N26 E pl N26 Cp d N27 E pl N27 Cp d N28 E pl N28 C}

_{p d N29 E pl N29 Cp d N30 E pl N30 Co}

_{p d N31 E pl N31 Cp d N32 E ple N32} -227- _Comp

_{d N33 E pl N33 Cp d N34 E pl N34 Co}

_{p d N35 E pl N35 Cp d N36 E pl N36 Co}

_{p d N37, E pl N37 Cp d N38, E pl N38 Co}

_{p d N39 E pl N39 Cp d N40 E pl N40} -228- _Co

_{p d N41, E pl N41 Cp d N42, E pl N42 Comp}

_{d N43 E pl N43 Cp d N44 E pl N44 Co}

_{p d N45 E pl N45 Cp d N46 E pl N46 C}

_{p d N47 E pl N47 Cp d N48 E pl N48} -229- _C

_{p d N49 E pl N49 Cp d N50 E pl N50 Co}

_{p d N51 E pl N51 Cp d N52 E pl N52 C}

_{p d N53 E pl N53 Cp d N54 E pl N54 C}

_{p d N55, E pl N55 Cp d N56, E pl N56} -230-

C

_{p d N57 E pl N57 Cp d N58 E pl N58 C}

_{p d N59, E pl N59 Cp d N60, E pl N60 C}

_{p d N61, E pl N61 Cp d N62, E pl N62} C

^{p d N63, E pl N63}

5 -231- ^{13. A compound as defined in claim 11 which is selected from}

C_{p d N46 E pl N46 Cp d N49 E pl N49}

_{Cp d N47 E pl N47} ^{Cp d N27 E pl N27}

C_{p d N48 E pl N48}

_{Cp d N43, E pl N43}

_Co

_{p d N50 E pl N50}

C_{p d N44 E pl N44} -232-

C^o

^{p d N45 E pl N45} _{Cp d N59, E pl N59}

_{Cop d N60 E pl N60}

C^d _{p d N63 E pl N63}

_Co

_{p d N62 E pl N62}

1^{4. A compound as defined in claim 13 which is selected from}

^C

^{p d N27 E pl N27 Cp d N43 E pl N43} -233-

C^o

^{p d N44 E pl N44} _{Cp d N60, E pl N60}

_Co

_{p d N45 E pl N45 Cp d N62, E pl N62}

_{Cp d N59 E pl N59}

^{Cdp d N63, E pl N63.} _{15. A compound as defined in claim 12 which is selected from}

C^ompou

^{d N60 E pl N60 d}

C_{p d N45, E pl N45} -234- ^{16. h Aete croomarpyolu mnodie atycc aotr pdoinsgitio ton Z a1n iyn a ocnceor odfan cclaeim wsith 1 th toe n 1u1m;b wehreinrgei ans R p5ro ivsid leindke ind F toorm thuela a Ir oyrl I oar. 17.e Ana cnotmiopmoeurn.d according to any one of claims 1 to 12; wherein said compound is the S- 18.e Ana cnotmiopmoeurn.d according to any one of claims 1 to 12; wherein said compound is the R- 19. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 18. 20. A us ceo amsp aou mnedd aiccincoer.ding to anyone of claims 1 to 18 or a composition according to claim 19 for 21. u Ase co inm tphoeu dniadg ancocsoisrd,i pnrgev toen atnioynon aend o/ofr cl tareimatsm 1en tot o 1f8 a o LrR aR cKo2m-kpionsaistieon as ascoccoiardteindg d tiose calasiem.19 for} _{22. u Ase co imnp tohuend dia agccnoorsdisin,g p troev aennytoionne o afnd c/laoirm tsre 1at tmoe 1n8t o orf a a co LmRpRoKs2it-iokinna asceco ardsisnogc tiaote cdlaim dis 1e9a for wheraesien o thre A LlzRhReiKm2e-rk’sin daisseea asses.ociated disease is se; dise a neurological disorders, such as Parkinson’s 23. c Ulasime o 1f9, a s cuoitmabpleou fnodr in ahsib diteinfigne thde in ac atnivyity on oef a o kfin claasime;s in 1 p taort 1ic8u,la orr a a L cRoRmKp2os kiitnioanse a.s defined in 24.1 U9s,e fo orf th ae c doimagpnoousnisd, a pcrecoverdnitniogn to an adn/yoorn treea otfm celanimt osf 1 a t LoR 1R8K o2r-k ain caosmep aosssiotiocinat aecdc doirsdeinagse to. claim 25. m Aet mhoedth coodm fporris tihneg a pdremviennistitoenrin agn tdo/o ar s turebajtment of a LRRK2-kinase associated disease; said of claims 1 to 19 or a composition accordinegc tto in cl naeimed 1 t2h.ereof a compound according to any one}